* 190090

SRC PROTOONCOGENE, NONRECEPTOR TYROSINE KINASE; SRC


Alternative titles; symbols

V-SRC AVIAN SARCOMA (SCHMIDT-RUPPIN A-2) VIRAL ONCOGENE
ONCOGENE SRC
PROTOONCOGENE SRC
SRC ONCOGENE
AVIAN SARCOMA VIRUS; ASV


HGNC Approved Gene Symbol: SRC

Cytogenetic location: 20q11.23     Genomic coordinates (GRCh38): 20:37,344,699-37,406,050 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
20q11.23 ?Thrombocytopenia 6 616937 AD 3
Colon cancer, advanced, somatic 114500 3

TEXT

Description

The SRC gene encodes a nonreceptor tyrosine kinase that is frequently implicated in cancer (summary by Turro et al., 2016).


Cloning and Expression

The SRC gene is homologous in sequence to the v-src gene of the Rous sarcoma virus (also called avian sarcoma virus, ASV) (Le Beau et al., 1984).


Gene Function

Azarnia et al. (1988) found that overexpression of the SRC gene in NIH 3T3 cells caused reduction of cell-to-cell transmission of molecules in the 400- to 700-dalton range. Downregulation was enhanced by point mutation of tyrosine-527, whereas mutation of tyrosine-416 suppressed both the downregulation of communication by the tyr-527 mutation and that by gene overexpression. The regulation of communication by SRC may be important in the control of embryonic development and cellular growth.

In membrane patches excised from mammalian central neurons, Yu et al. (1997) found that Src regulated the activity of NMDA channels at synapses and coprecipitated with NMDA receptor (NMDAR) proteins. The findings suggested that NMDA receptor regulation by Src may be important in development, plasticity, and pathology in the CNS.

Luttrell et al. (1999) demonstrated that c-src binds to the amino terminus of beta-arrestin-1 (107940) in a complex resulting from the stimulation of beta-2 adrenergic receptors (see 109690). Activated beta-2-adrenergic receptor bound beta-arrestin-1, which then bound c-src. This interaction targeted the complex to clathrin-coated pits and allowed for beta-2-adrenergic activation of the MAP kinases ERK1 (601795) and ERK2 (176948).

TRANCE (602642), a TNF family member, and its receptor, RANK (603499), are critical regulators of dendritic cell and osteoclast function. Wong et al. (1999) demonstrated that TRANCE activates the antiapoptotic serine/threonine kinase PKB (AKT1; 164730) through a signaling complex involving SRC and TRAF6 (602355). A deficiency in SRC or addition of SRC family kinase inhibitors blocked TRANCE-mediated PKB activation in osteoclasts. SRC and TRAF6 interacted with each other and with RANK upon receptor engagement. TRAF6, in turn, enhanced the kinase activity of SRC, leading to tyrosine phosphorylation of downstream signaling molecules such as CBL (165360). These results defined a mechanism by which TRANCE activates SRC family kinases and PKB, and provided evidence of cross-talk between TRAF proteins and SRC family kinases.

Using a colon cancer cell line, Avizienyte et al. (2002) studied the role of SRC in cell adhesion and metastasis. Transfection and overexpression of a constitutively active SRC mutant reduced cell-cell contacts and caused redistribution of adherens junction components to discrete adhesion-like structures at the tips of membrane protrusions. Expression of active SRC also impaired the movement of E-cadherin (192090) from the cell interior to the plasma membrane following exposure to high calcium. Avizienyte et al. (2002) provided evidence that the alpha-V (193210) and beta-1 (135630) integrins and FAK (600758) were required for the adhesion changes induced by SRC.

Sandilands et al. (2004) found that RhoB (165370) colocalized with active Src in the cytoplasm of mouse embryonic fibroblasts, and they presented evidence that RhoB is a component of 'outside-in' signaling pathways that coordinate Src activation with translocation to transmembrane receptors.

Yeung et al. (2006) devised genetically encoded probes to assess surface potential in intact cells. These probes revealed marked, localized alterations in the change of the inner surface of the plasma membrane of macrophages during the course of phagocytosis. Hydrolysis of phosphoinositides and displacement of phosphatidylserine accounted for the change in surface potential at the phagosomal cup. Signaling molecules such as KRAS (190070), RAC1 (602048), and c-SRC that are targeted to the membrane by electrostatic interactions were rapidly released from membrane subdomains where the surface charge was altered by lipid remodeling during phagocytosis.

The predominant tyrosine kinase mediating NMDAR tyrosine phosphorylation is SRC, which enhances NMDAR channel activity. NMDAR hypofunction is considered a key detrimental consequence of excessive NRG1 (142445)-ErbB4 (600543) signaling found in people with schizophrenia (181500). Using whole cell recordings of mouse hippocampal slices, Pitcher et al. (2011) found that Nrg1-beta-ErbB4 signaling blocked Src kinase-induced enhancement of NMDAR excitatory currents. However, the Nrg1-ErbB4 signaling pathway did not affect basal NMDAR function. Similar results were observed in pyramidal cells in the prefrontal cortex. Nrg1-beta also prevented long-term potentiation of synaptic transmission induced by theta-burst stimulation. The study identified Src as a downstream target of the Nrg1-beta-ErbB4 signaling pathway, and indicated that Src activity is an essential step in regulating synaptic plasticity.

Using immunofluorescence analysis, Reinecke et al. (2014) showed that SRC colocalized with MICALL1 (619563) along tubular membranes that radiated from the endocytic recycling compartment (ERC) in HeLa cells under steady-state conditions. MICALL1 interacted with SRC and was required for SRC activation and transport from perinuclear region to the plasma membrane upon epidermal growth factor (EGF; 131530) stimulation. Likewise, MICALL1 colocalized with SRC in human foreskin fibroblasts and was required for SRC recruitment to circular dorsal ruffles (CDRs) following platelet-derived growth factor (PDGF; see 173430) stimulation. MICALL1 was also required for PDGF-induced focal adhesion turnover. The results indicated that MICALL1 regulates transport of active SRC to focal adhesions, thereby controlling turnover of focal adhesions. Further analysis revealed that MICALL1 regulated cell spreading and was required for migration of human foreskin fibroblasts. Knockdown analysis in HeLa cells demonstrated that EHD1 (605888) was required for SRC transport and activation and acted as a molecular 'pinchase' on MICALL1 tubules to release SRC from the ERC in response to EGF. Inactivated SRC was maintained at the ERC. Upon EGF stimulation, SRC was sorted into MICALL1-decorated tubular recycling endosomes (REs) and became partially activated. EHD1 was recruited to tubular REs by MICALL1, where it vesiculated REs that contained SRC and were transported to the plasma membrane, where SRC became fully activated to mediate rearrangement of the actin cytoskeletal CDRs, focal adhesion disassembly, and cell migration.

Taniguchi et al. (2015) showed in mice and human cells that GP130 (600694), a coreceptor for IL6 (147620) cytokines, triggers activation of YAP (606608) and Notch (190198), transcriptional regulators that control tissue growth and regeneration, independently of the GP130 effector STAT3 (102582). Through YAP and Notch, intestinal GP130 signaling stimulates epithelial cell proliferation, causes aberrant differentiation, and confers resistance to mucosal erosion. GP130 associates with the related tyrosine kinases SRC and YES (164880), which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signaling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.

Lievens et al. (2016) reported that mouse Zdhhc3 (617150) catalyzed S-palmitoylation of the transmembrane isoforms of Ncam1 (116930), Ncam140 and Ncam180. Using site-directed mutagenesis and inhibitor studies, they showed that Fgf2 (134920) induced phosphorylation of Zdhhc3 on tyr18 via the tyrosine kinase activity of its receptor, Fgfr1 (136350). Src directly phosphorylated Zdhhc3 on tyr295 and tyr297. The 2 kinases had opposite effects on Zdhhc3 activity, with Fgfr1-dependent phosphorylation enhancing Zdhhc3 activity, and Src-dependent phosphorylation inhibiting Zdhhc3 activity. Autopalmitoylation, an intermediate reaction state in palmitate transfer to target proteins, was enhanced by absence of all 5 tyrosines in Zdhhc3 and was abolished with the dominant-negative cys157-to-ser (C157S) mutation at the active site of Zdhhc3. Overexpression of tyrosine-mutant Zdhhc3 in cultured rat hippocampal neurons increased the number of neurites and tended to increase neurite length. Lievens et al. (2016) concluded that FGF2-FGFR1 signaling facilitates ZDHHC3 tyrosine phosphorylation and triggers NCAM1 palmitoylation for neurite extension, whereas SRC-mediated ZDHHC3 phosphorylation inhibits NCAM1 palmitoylation and neurite extension.


Mapping

The human SRC protooncogene was assigned to chromosome 20 by somatic cell hybrid studies (Sakaguchi et al., 1982). Le Beau et al. (1984) assigned the SRC gene to 20q12-q13 by in situ hybridization. Lebo et al. (1984) and Parker et al. (1985) confirmed the assignment by dual-beam chromosome sorting and spot blot DNA analysis.

By in situ hybridization, Morris et al. (1989) placed the SRC gene at 20q11.2. They observed a secondary peak of grains in the region 20q13.2-qter, the localization of SRC suggested by previous in situ studies. The new assignment, 20q11.2, is consistent with the assignment of HCK (142370) which presumably belongs to the same gene family, having originated from a common ancestral gene.


Molecular Genetics

Somatic Changes in Cancer

Le Beau et al. (1985) found that deletions of 20q in myeloid disorders were actually interstitial, although they appeared to be terminal.

Morris et al. (1989) found that 1 allele of the SRC gene was lost in 2 patients with leukemia and a deletion in 20q. They suggested that the deletions were interstitial.

Elevated c-src tyrosine kinase activity has been found in colon cancers, particularly in those metastatic to the liver. Studies of the mechanism of SRC regulation suggested that SRC kinase activity is downregulated by phosphorylation of a critical C-terminal tyrosine (tyr530 in human SRC, equivalent to tyr527 in chicken Src) and have implied the existence of activating mutations in this C-terminal regulatory region. Irby et al. (1999) reported the identification of a truncating mutation in SRC (Q531X; 190090.0001) in 12% of cases of advanced human colon cancer tested and demonstrated that the mutation is activating, transforming, tumorigenic, and metastasis-promoting. The results provided, for the first time, genetic evidence that activating SRC mutations may have a role in the malignant progression of human colon cancer.

Thrombocytopenia 6

In affected members of a 3-generation family with thrombocytopenia-6 (THC6; 616937), Turro et al. (2016) identified a heterozygous missense mutation in the SRC gene (E527K; 190090.0002). The mutation was found by exome sequencing and segregated with the disorder in the family. Studies of patient platelets and in vitro transfection studies indicated that the mutation resulted in constitutive activation of the SRC kinase in a dominant manner. These changes were associated with defective megakaryopoiesis and abnormal proplatelet formation.


Animal Model

By homologous recombination in mouse embryonic stem (ES) cells, Soriano et al. (1991) produced mice carrying a null mutation in the SRC gene. Two independently targeted clones were used to generate chimeras that transmitted the mutated allele to their offspring. Intercrossing of heterozygotes gave rise to live-born homozygotes, but most of these mice died within the first few weeks of birth. Histologic and hematologic examination of the homozygous mutants did not show detectable abnormalities in the brain or platelets, where SRC is most highly expressed. Deficiency in bone remodeling, indicating impaired osteoclast function and leading to osteopetrosis, was found, however. These results showed that SRC is not required for general cell viability, possibly because of functional overlap with other related tyrosine kinases such as YES (164880), HCK, FGR (164940), and LYN (165120), and uncovered an essential role for SRC in bone formation.

Lowe et al. (1993) used in vitro approaches and fetal liver transplantation into irradiated SRC-deficient mice to demonstrate that the inherent defect resulting in osteopetrosis is in osteoclasts and is autonomous of the bone marrow microenvironment. They identified a cell type in which SRC function is essential and cannot be replaced by other related kinases. Lowe et al. (1993) suggested that it should be possible to isolate the substrate that is specific to SRC.

Xing et al. (2001) found that expression of a truncated Src mutant lacking the kinase domain induced osteopetrosis in wildtype and Src +/- mice and worsened osteopetrosis in Src -/- mice by increased osteoclast apoptosis. Induction of apoptosis by this mutant required a functional SH2 domain, but not the SH3 domain, and was associated with reduced Akt kinase activity.

Schinke et al. (2009) analyzed 2 osteopetrotic mouse models, Src-deficient mice and Tcirg1 (604592)-deficient (oc/oc) mice, and observed that contact radiographs at 2 weeks of age revealed an osteopetrorickets phenotype specifically in oc/oc mice, in which high bone mass was accompanied by rachitic widening of the growth plates and by severe growth retardation, 2 characteristics not seen in Src -/- mice. Nondecalcified histology confirmed that only oc/oc mice had a demineralization defect of hypertrophic cartilage and bone matrix, whereas in Src -/- mice the increased bone matrix was normally mineralized. Quantification of these observations by histomorphometry confirmed that Src -/- mice displayed osteopetrosis, whereas oc/oc mice displayed osteopetrorickets, demonstrating that osteoclast dysfunction does not necessarily cause a defect in skeletal mineralization. After demonstrating that hypochlorhydria is associated with Tcirg1 deficiency. Schinke et al. (2009) generated mice with a combined deficiency in both Src and Cckbr (118445), which encodes a gastrin receptor that affects acid secretion by parietal cells, and observed the development of osteopetrorickets, a phenotype not seen in Cckbr -/- mice or in Src -/- mice. Schinke et al. (2009) concluded that osteopetrosis and osteopetrorickets are distinct phenotypes, depending on the site or sites of defective acidification.


ALLELIC VARIANTS ( 2 Selected Examples):

.0001 COLON CANCER, ADVANCED, SOMATIC

SRC, GLN531TER
  
RCV000013401...

Irby et al. (1999) identified a C-to-T transition in codon 531, which changed the codon from gln to stop (Q531X). As the mutation in codon 531 generated an ScaI site, they were able to develop a rapid screen for the SRC codon 531 mutation. The mutation was found in 12% of advanced human colon cancer (114500) tumors tested. The mutation was not identified in primary, early stage, human colon cancer specimens or in normal genomic DNA from patients with tumors harboring the SRC codon 531 mutation.


.0002 THROMBOCYTOPENIA 6 (1 family)

SRC, GLU527LYS
  
RCV000211002...

In affected members of a 3-generation family with thrombocytopenia-6 (THC6; 616937), Turro et al. (2016) identified a heterozygous c.1579G-A transition in the SRC gene, resulting in a glu527-to-lys (E527K) substitution at a conserved residue in the kinase domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the ExAC database or in 2,974 in-house control subjects. In vitro functional expression assays showed that the mutation resulted in high kinase activity compared to wildtype, consistent with a dominant gain of function. Immunoblot analysis of patient cells showed increased levels of active SRC and overall increased tyrosine phosphorylation compared to controls. Transfection of the mutation into control blood stem cells caused defective megakaryopoiesis associated with increased overall tyrosine phosphorylation in megakaryocytes. Compared with control conditions, more megakaryocytes were immature and had defects in proplatelet formation, with alterations in the actin cytoskeleton and podosome structures when adhered to fibrinogen. These abnormalities resembled those found in patient bone marrow biopsies and could be rescued using an SRC inhibitor. Expression of the mutation in zebrafish embryos resulted in abnormal early primitive hematopoiesis, thrombocytopenia, and smaller bones compared to controls.


REFERENCES

  1. Avizienyte, E., Wyke, A. W., Jones, R. J., McLean, G. W., Westhoff, M. A., Brunton, V. G., Frame, M. C. Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signalling. Nature Cell Biol. 4: 632-638, 2002. [PubMed: 12134161, related citations] [Full Text]

  2. Azarnia, R., Reddy, S., Kmiecik, T. E., Shalloway, D., Loewenstein, W. R. The cellular src gene product regulates junctional cell-to-cell communication. Science 239: 398-401, 1988. [PubMed: 2447651, related citations] [Full Text]

  3. Czernilofsky, A. P., Levinson, A. D., Varmus, H. E., Bishop, J. M., Tischer, E., Goodman, H. Correction to the nucleotide sequence of the src gene of Rous sarcoma virus. Nature 301: 736-738, 1983. [PubMed: 6298633, related citations] [Full Text]

  4. Gibbs, C. P., Tanaka, A., Anderson, S. K., Radul, J., Baar, J., Ridgway, A., Kung, H.-J., Fujita, D. J. Isolation and structural mapping of a human c-src gene homologous to the transforming gene (v-src) of Rous sarcoma virus. J. Virol. 53: 19-24, 1985. [PubMed: 2981336, related citations] [Full Text]

  5. Irby, R. B., Mao, W., Coppola, D., Kang, J., Loubeau, J. M., Trudeau, W., Karl, R., Fujita, D. J., Jove, R., Yeatman, T. J. Activating SRC mutation in a subset of advanced human colon cancers. Nature Genet. 21: 187-190, 1999. [PubMed: 9988270, related citations] [Full Text]

  6. Le Beau, M. M., Westbrook, C. A., Diaz, M. O., Rowley, J. D. Evidence for two distinct c-src loci on human chromosomes 1 and 20. Nature 312: 70-71, 1984. [PubMed: 6092965, related citations] [Full Text]

  7. Le Beau, M. M., Westbrook, C. A., Diaz, M. O., Rowley, J. D. c-src is consistently conserved in the chromosomal deletion (20q) observed in myeloid disorders. Proc. Nat. Acad. Sci. 82: 6692-6696, 1985. [PubMed: 2413444, related citations] [Full Text]

  8. Lebo, R. V., Cheung, M.-C., Bruce, B. D. Rapid gene mapping by dual laser chromosome sorting and spot blot DNA analysis. (Abstract) Am. J. Hum. Genet. 36: 101S, 1984.

  9. Lievens, P. M.-J., Kuznetsova, T., Kochlasmazashvili, G., Cesca, F., Gorinski, N., Galil, D. A., Cherkas, V., Ronkina, N., Lafera, J., Gaestel, M., Ponimaskin, E. ZDHHC3 tyrosine phosphorylation regulates neural cell adhesion molecule palmitoylation. Molec. Cell. Biol. 36: 2208-2225, 2016. [PubMed: 27247265, images, related citations] [Full Text]

  10. Lowe, C., Yoneda, T., Boyce, B. F., Chen, H., Mundy, G. R., Soriano, P. Osteopetrosis in Src-deficient mice is due to an autonomous defect of osteoclasts. Proc. Nat. Acad. Sci. 90: 4485-4489, 1993. [PubMed: 7685105, related citations] [Full Text]

  11. Luttrell, L. M., Ferguson, S. S. G., Daaka, Y., Miller, W. E., Maudsley, S., Della Rocca, G. J., Lin, F.-T., Kawakatsu, H., Owada, K., Luttrell, D. K., Caron, M. G., Lefkowitz, R. J. Beta-arrestin-dependent formation of beta-2 adrenergic receptor-Src protein kinase complexes. Science 283: 655-661, 1999. [PubMed: 9924018, related citations] [Full Text]

  12. Morris, C. M., Honeybone, L. M., Hollings, P. E., Fitzgerald, P. H. Localization of the SRC oncogene to chromosome band 20q11.2 and loss of this gene with deletion (20q) in two leukemic patients. Blood 74: 1768-1773, 1989. [PubMed: 2506951, related citations]

  13. Parker, R. C., Mardon, G., Lebo, R. V., Varmus, H. E., Bishop, J. M. Isolation of duplicated human c-src genes located on chromosomes 1 and 20. Molec. Cell. Biol. 5: 831-838, 1985. [PubMed: 2581127, related citations] [Full Text]

  14. Pitcher, G. M., Kalia, L. V., Ng, D., Goodfellow, N. M., Yee, K. T., Lambe, E. K., Salter, M. W. Schizophrenia susceptibility pathway neuregulin 1-ErbB4 suppresses Src upregulation of NMDA receptors. Nature Med. 17: 470-478, 2011. [PubMed: 21441918, images, related citations] [Full Text]

  15. Reinecke, J. B., Katafiasz, D., Naslavsky, N., Caplan, S. Regulation of Src trafficking and activation by the endocytic regulatory proteins MICAL-L1 and EHD1. J. Cell Sci. 127: 1684-1698, 2014. [PubMed: 24481818, images, related citations] [Full Text]

  16. Sakaguchi, A. Y., Mohandas, T., Naylor, S. L. A human c-src gene resides on the proximal long arm of chromosome 20 (cen-q13.1). Cancer Genet. Cytogenet. 18: 123-129, 1985. [PubMed: 2996754, related citations] [Full Text]

  17. Sakaguchi, A. Y., Naylor, S. L., Weinberg, R. A., Shows, T. B. Organization of human proto-oncogenes. (Abstract) Am. J. Hum. Genet. 34: 175A, 1982.

  18. Sakaguchi, A. Y., Zabel, B. U., Grzeschik, K. H., Law, M. L., Naylor, S. L. Human proto-oncogene assignments. (Abstract) Cytogenet. Cell Genet. 37: 572-573, 1984.

  19. Sandilands, E., Cans, C., Fincham, V. J., Brunton, V. G., Mellor, H., Prendergast, G. C., Norman, J. C., Superti-Furga, G., Frame, M. C. RhoB and actin polymerization coordinate Src activation with endosome-mediated delivery to the membrane. Dev. Cell 7: 855-869, 2004. [PubMed: 15572128, related citations] [Full Text]

  20. Schinke, T., Schilling, A. F., Baranowsky, A., Seitz, S., Marshall, R. P., Linn, T., Blaeker, M., Huebner, A. K., Schulz, A., Simon, R., Gebauer, M., Priemel, M., and 15 others. Impaired gastric acidification negatively affects calcium homeostasis and bone mass. Nature Med. 15: 674-681, 2009. [PubMed: 19448635, related citations] [Full Text]

  21. Soriano, P., Montgomery, C., Geske, R., Bradley, A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64: 693-702, 1991. [PubMed: 1997203, related citations] [Full Text]

  22. Taniguchi, K., Wu, L.-W., Grivennikov, S. I., de Jong, P. R., Lian, I., Yu, F.-X., Wang, K., Ho, S. B., Boland, B. S., Chang, J. T., Sandborn, W. J., Hardiman, G., Raz, E., Maehara, Y., Yoshimura, A., Zucman-Rossi, J., Guan, K.-L., Karin, M. A gp130-Src-YAP module links inflammation to epithelial regeneration. Nature 519: 57-62, 2015. [PubMed: 25731159, images, related citations] [Full Text]

  23. Turro, E., Greene, D., Wijgaerts, A., Thys, C., Lentaigne, C., Bariana, T. K., Westbury, S. J., Kelly, A. M., Selleslag, D., Stephens, J. C., Papadia, S., Simeoni, I., and 32 others. A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies. Sci. Transl. Med. 8: 328ra30, 2016. Note: Electronic Article. [PubMed: 26936507, images, related citations] [Full Text]

  24. Wong, B. R., Besser, D., Kim, N., Arron, J. R., Vologodskaia, M., Hanafusa, H., Choi, Y. TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Molec. Cell 4: 1041-1049, 1999. [PubMed: 10635328, related citations] [Full Text]

  25. Xing, L., Venegas, A. M., Chen, A., Garrett-Beal, L., Boyce, B. F., Varmus, H. E., Schwartzberg, P. L. Genetic evidence for a role for Src family kinases in TNF family receptor signaling and cell survival. Genes Dev. 15: 241-253, 2001. [PubMed: 11157779, images, related citations] [Full Text]

  26. Yeung, T., Terebiznik, M., Yu, L., Silvius, J., Abidi, W. M., Philips, M., Levine, T., Kapus, A., Grinstein, S. Receptor activation alters inner surface potential during phagocytosis. Science 313: 347-351, 2006. [PubMed: 16857939, related citations] [Full Text]

  27. Yu, X.-M., Askalan, R., Keil, G. J, II, Salter, M. W. NMDA channel regulation by channel-associated protein tyrosine kinase Src. Science 275: 674-678, 1997. [PubMed: 9005855, related citations] [Full Text]


Bao Lige - updated : 10/12/2021
Patricia A. Hartz - updated : 10/07/2016
Cassandra L. Kniffin - updated : 5/3/2016
Ada Hamosh - updated : 6/3/2015
Cassandra L. Kniffin - updated : 9/6/2011
Marla J. F. O'Neill - updated : 8/4/2009
Ada Hamosh - updated : 11/28/2006
Patricia A. Hartz - updated : 1/6/2005
Patricia A. Hartz - updated : 12/17/2002
Stylianos E. Antonarakis - updated : 1/7/2000
Ada Hamosh - updated : 2/1/1999
Victor A. McKusick - updated : 1/28/1999
Creation Date:
Victor A. McKusick : 6/2/1986
mgross : 10/12/2021
carol : 01/28/2021
mgross : 10/07/2016
carol : 09/02/2016
alopez : 05/06/2016
alopez : 5/4/2016
ckniffin : 5/3/2016
alopez : 6/3/2015
carol : 6/23/2014
joanna : 6/22/2014
carol : 9/7/2011
ckniffin : 9/6/2011
wwang : 8/10/2009
terry : 8/4/2009
terry : 8/4/2009
alopez : 12/7/2006
terry : 11/28/2006
mgross : 1/7/2005
terry : 1/6/2005
mgross : 1/3/2003
terry : 12/17/2002
mgross : 1/7/2000
alopez : 2/1/1999
alopez : 2/1/1999
terry : 1/28/1999
psherman : 6/6/1998
mark : 3/18/1996
carol : 11/22/1993
carol : 6/17/1993
supermim : 3/16/1992
carol : 2/24/1992
carol : 3/12/1991
supermim : 3/20/1990

* 190090

SRC PROTOONCOGENE, NONRECEPTOR TYROSINE KINASE; SRC


Alternative titles; symbols

V-SRC AVIAN SARCOMA (SCHMIDT-RUPPIN A-2) VIRAL ONCOGENE
ONCOGENE SRC
PROTOONCOGENE SRC
SRC ONCOGENE
AVIAN SARCOMA VIRUS; ASV


HGNC Approved Gene Symbol: SRC

Cytogenetic location: 20q11.23     Genomic coordinates (GRCh38): 20:37,344,699-37,406,050 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
20q11.23 ?Thrombocytopenia 6 616937 Autosomal dominant 3
Colon cancer, advanced, somatic 114500 3

TEXT

Description

The SRC gene encodes a nonreceptor tyrosine kinase that is frequently implicated in cancer (summary by Turro et al., 2016).


Cloning and Expression

The SRC gene is homologous in sequence to the v-src gene of the Rous sarcoma virus (also called avian sarcoma virus, ASV) (Le Beau et al., 1984).


Gene Function

Azarnia et al. (1988) found that overexpression of the SRC gene in NIH 3T3 cells caused reduction of cell-to-cell transmission of molecules in the 400- to 700-dalton range. Downregulation was enhanced by point mutation of tyrosine-527, whereas mutation of tyrosine-416 suppressed both the downregulation of communication by the tyr-527 mutation and that by gene overexpression. The regulation of communication by SRC may be important in the control of embryonic development and cellular growth.

In membrane patches excised from mammalian central neurons, Yu et al. (1997) found that Src regulated the activity of NMDA channels at synapses and coprecipitated with NMDA receptor (NMDAR) proteins. The findings suggested that NMDA receptor regulation by Src may be important in development, plasticity, and pathology in the CNS.

Luttrell et al. (1999) demonstrated that c-src binds to the amino terminus of beta-arrestin-1 (107940) in a complex resulting from the stimulation of beta-2 adrenergic receptors (see 109690). Activated beta-2-adrenergic receptor bound beta-arrestin-1, which then bound c-src. This interaction targeted the complex to clathrin-coated pits and allowed for beta-2-adrenergic activation of the MAP kinases ERK1 (601795) and ERK2 (176948).

TRANCE (602642), a TNF family member, and its receptor, RANK (603499), are critical regulators of dendritic cell and osteoclast function. Wong et al. (1999) demonstrated that TRANCE activates the antiapoptotic serine/threonine kinase PKB (AKT1; 164730) through a signaling complex involving SRC and TRAF6 (602355). A deficiency in SRC or addition of SRC family kinase inhibitors blocked TRANCE-mediated PKB activation in osteoclasts. SRC and TRAF6 interacted with each other and with RANK upon receptor engagement. TRAF6, in turn, enhanced the kinase activity of SRC, leading to tyrosine phosphorylation of downstream signaling molecules such as CBL (165360). These results defined a mechanism by which TRANCE activates SRC family kinases and PKB, and provided evidence of cross-talk between TRAF proteins and SRC family kinases.

Using a colon cancer cell line, Avizienyte et al. (2002) studied the role of SRC in cell adhesion and metastasis. Transfection and overexpression of a constitutively active SRC mutant reduced cell-cell contacts and caused redistribution of adherens junction components to discrete adhesion-like structures at the tips of membrane protrusions. Expression of active SRC also impaired the movement of E-cadherin (192090) from the cell interior to the plasma membrane following exposure to high calcium. Avizienyte et al. (2002) provided evidence that the alpha-V (193210) and beta-1 (135630) integrins and FAK (600758) were required for the adhesion changes induced by SRC.

Sandilands et al. (2004) found that RhoB (165370) colocalized with active Src in the cytoplasm of mouse embryonic fibroblasts, and they presented evidence that RhoB is a component of 'outside-in' signaling pathways that coordinate Src activation with translocation to transmembrane receptors.

Yeung et al. (2006) devised genetically encoded probes to assess surface potential in intact cells. These probes revealed marked, localized alterations in the change of the inner surface of the plasma membrane of macrophages during the course of phagocytosis. Hydrolysis of phosphoinositides and displacement of phosphatidylserine accounted for the change in surface potential at the phagosomal cup. Signaling molecules such as KRAS (190070), RAC1 (602048), and c-SRC that are targeted to the membrane by electrostatic interactions were rapidly released from membrane subdomains where the surface charge was altered by lipid remodeling during phagocytosis.

The predominant tyrosine kinase mediating NMDAR tyrosine phosphorylation is SRC, which enhances NMDAR channel activity. NMDAR hypofunction is considered a key detrimental consequence of excessive NRG1 (142445)-ErbB4 (600543) signaling found in people with schizophrenia (181500). Using whole cell recordings of mouse hippocampal slices, Pitcher et al. (2011) found that Nrg1-beta-ErbB4 signaling blocked Src kinase-induced enhancement of NMDAR excitatory currents. However, the Nrg1-ErbB4 signaling pathway did not affect basal NMDAR function. Similar results were observed in pyramidal cells in the prefrontal cortex. Nrg1-beta also prevented long-term potentiation of synaptic transmission induced by theta-burst stimulation. The study identified Src as a downstream target of the Nrg1-beta-ErbB4 signaling pathway, and indicated that Src activity is an essential step in regulating synaptic plasticity.

Using immunofluorescence analysis, Reinecke et al. (2014) showed that SRC colocalized with MICALL1 (619563) along tubular membranes that radiated from the endocytic recycling compartment (ERC) in HeLa cells under steady-state conditions. MICALL1 interacted with SRC and was required for SRC activation and transport from perinuclear region to the plasma membrane upon epidermal growth factor (EGF; 131530) stimulation. Likewise, MICALL1 colocalized with SRC in human foreskin fibroblasts and was required for SRC recruitment to circular dorsal ruffles (CDRs) following platelet-derived growth factor (PDGF; see 173430) stimulation. MICALL1 was also required for PDGF-induced focal adhesion turnover. The results indicated that MICALL1 regulates transport of active SRC to focal adhesions, thereby controlling turnover of focal adhesions. Further analysis revealed that MICALL1 regulated cell spreading and was required for migration of human foreskin fibroblasts. Knockdown analysis in HeLa cells demonstrated that EHD1 (605888) was required for SRC transport and activation and acted as a molecular 'pinchase' on MICALL1 tubules to release SRC from the ERC in response to EGF. Inactivated SRC was maintained at the ERC. Upon EGF stimulation, SRC was sorted into MICALL1-decorated tubular recycling endosomes (REs) and became partially activated. EHD1 was recruited to tubular REs by MICALL1, where it vesiculated REs that contained SRC and were transported to the plasma membrane, where SRC became fully activated to mediate rearrangement of the actin cytoskeletal CDRs, focal adhesion disassembly, and cell migration.

Taniguchi et al. (2015) showed in mice and human cells that GP130 (600694), a coreceptor for IL6 (147620) cytokines, triggers activation of YAP (606608) and Notch (190198), transcriptional regulators that control tissue growth and regeneration, independently of the GP130 effector STAT3 (102582). Through YAP and Notch, intestinal GP130 signaling stimulates epithelial cell proliferation, causes aberrant differentiation, and confers resistance to mucosal erosion. GP130 associates with the related tyrosine kinases SRC and YES (164880), which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signaling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.

Lievens et al. (2016) reported that mouse Zdhhc3 (617150) catalyzed S-palmitoylation of the transmembrane isoforms of Ncam1 (116930), Ncam140 and Ncam180. Using site-directed mutagenesis and inhibitor studies, they showed that Fgf2 (134920) induced phosphorylation of Zdhhc3 on tyr18 via the tyrosine kinase activity of its receptor, Fgfr1 (136350). Src directly phosphorylated Zdhhc3 on tyr295 and tyr297. The 2 kinases had opposite effects on Zdhhc3 activity, with Fgfr1-dependent phosphorylation enhancing Zdhhc3 activity, and Src-dependent phosphorylation inhibiting Zdhhc3 activity. Autopalmitoylation, an intermediate reaction state in palmitate transfer to target proteins, was enhanced by absence of all 5 tyrosines in Zdhhc3 and was abolished with the dominant-negative cys157-to-ser (C157S) mutation at the active site of Zdhhc3. Overexpression of tyrosine-mutant Zdhhc3 in cultured rat hippocampal neurons increased the number of neurites and tended to increase neurite length. Lievens et al. (2016) concluded that FGF2-FGFR1 signaling facilitates ZDHHC3 tyrosine phosphorylation and triggers NCAM1 palmitoylation for neurite extension, whereas SRC-mediated ZDHHC3 phosphorylation inhibits NCAM1 palmitoylation and neurite extension.


Mapping

The human SRC protooncogene was assigned to chromosome 20 by somatic cell hybrid studies (Sakaguchi et al., 1982). Le Beau et al. (1984) assigned the SRC gene to 20q12-q13 by in situ hybridization. Lebo et al. (1984) and Parker et al. (1985) confirmed the assignment by dual-beam chromosome sorting and spot blot DNA analysis.

By in situ hybridization, Morris et al. (1989) placed the SRC gene at 20q11.2. They observed a secondary peak of grains in the region 20q13.2-qter, the localization of SRC suggested by previous in situ studies. The new assignment, 20q11.2, is consistent with the assignment of HCK (142370) which presumably belongs to the same gene family, having originated from a common ancestral gene.


Molecular Genetics

Somatic Changes in Cancer

Le Beau et al. (1985) found that deletions of 20q in myeloid disorders were actually interstitial, although they appeared to be terminal.

Morris et al. (1989) found that 1 allele of the SRC gene was lost in 2 patients with leukemia and a deletion in 20q. They suggested that the deletions were interstitial.

Elevated c-src tyrosine kinase activity has been found in colon cancers, particularly in those metastatic to the liver. Studies of the mechanism of SRC regulation suggested that SRC kinase activity is downregulated by phosphorylation of a critical C-terminal tyrosine (tyr530 in human SRC, equivalent to tyr527 in chicken Src) and have implied the existence of activating mutations in this C-terminal regulatory region. Irby et al. (1999) reported the identification of a truncating mutation in SRC (Q531X; 190090.0001) in 12% of cases of advanced human colon cancer tested and demonstrated that the mutation is activating, transforming, tumorigenic, and metastasis-promoting. The results provided, for the first time, genetic evidence that activating SRC mutations may have a role in the malignant progression of human colon cancer.

Thrombocytopenia 6

In affected members of a 3-generation family with thrombocytopenia-6 (THC6; 616937), Turro et al. (2016) identified a heterozygous missense mutation in the SRC gene (E527K; 190090.0002). The mutation was found by exome sequencing and segregated with the disorder in the family. Studies of patient platelets and in vitro transfection studies indicated that the mutation resulted in constitutive activation of the SRC kinase in a dominant manner. These changes were associated with defective megakaryopoiesis and abnormal proplatelet formation.


Animal Model

By homologous recombination in mouse embryonic stem (ES) cells, Soriano et al. (1991) produced mice carrying a null mutation in the SRC gene. Two independently targeted clones were used to generate chimeras that transmitted the mutated allele to their offspring. Intercrossing of heterozygotes gave rise to live-born homozygotes, but most of these mice died within the first few weeks of birth. Histologic and hematologic examination of the homozygous mutants did not show detectable abnormalities in the brain or platelets, where SRC is most highly expressed. Deficiency in bone remodeling, indicating impaired osteoclast function and leading to osteopetrosis, was found, however. These results showed that SRC is not required for general cell viability, possibly because of functional overlap with other related tyrosine kinases such as YES (164880), HCK, FGR (164940), and LYN (165120), and uncovered an essential role for SRC in bone formation.

Lowe et al. (1993) used in vitro approaches and fetal liver transplantation into irradiated SRC-deficient mice to demonstrate that the inherent defect resulting in osteopetrosis is in osteoclasts and is autonomous of the bone marrow microenvironment. They identified a cell type in which SRC function is essential and cannot be replaced by other related kinases. Lowe et al. (1993) suggested that it should be possible to isolate the substrate that is specific to SRC.

Xing et al. (2001) found that expression of a truncated Src mutant lacking the kinase domain induced osteopetrosis in wildtype and Src +/- mice and worsened osteopetrosis in Src -/- mice by increased osteoclast apoptosis. Induction of apoptosis by this mutant required a functional SH2 domain, but not the SH3 domain, and was associated with reduced Akt kinase activity.

Schinke et al. (2009) analyzed 2 osteopetrotic mouse models, Src-deficient mice and Tcirg1 (604592)-deficient (oc/oc) mice, and observed that contact radiographs at 2 weeks of age revealed an osteopetrorickets phenotype specifically in oc/oc mice, in which high bone mass was accompanied by rachitic widening of the growth plates and by severe growth retardation, 2 characteristics not seen in Src -/- mice. Nondecalcified histology confirmed that only oc/oc mice had a demineralization defect of hypertrophic cartilage and bone matrix, whereas in Src -/- mice the increased bone matrix was normally mineralized. Quantification of these observations by histomorphometry confirmed that Src -/- mice displayed osteopetrosis, whereas oc/oc mice displayed osteopetrorickets, demonstrating that osteoclast dysfunction does not necessarily cause a defect in skeletal mineralization. After demonstrating that hypochlorhydria is associated with Tcirg1 deficiency. Schinke et al. (2009) generated mice with a combined deficiency in both Src and Cckbr (118445), which encodes a gastrin receptor that affects acid secretion by parietal cells, and observed the development of osteopetrorickets, a phenotype not seen in Cckbr -/- mice or in Src -/- mice. Schinke et al. (2009) concluded that osteopetrosis and osteopetrorickets are distinct phenotypes, depending on the site or sites of defective acidification.


ALLELIC VARIANTS 2 Selected Examples):

.0001   COLON CANCER, ADVANCED, SOMATIC

SRC, GLN531TER
SNP: rs121913314, ClinVar: RCV000013401, RCV000428592

Irby et al. (1999) identified a C-to-T transition in codon 531, which changed the codon from gln to stop (Q531X). As the mutation in codon 531 generated an ScaI site, they were able to develop a rapid screen for the SRC codon 531 mutation. The mutation was found in 12% of advanced human colon cancer (114500) tumors tested. The mutation was not identified in primary, early stage, human colon cancer specimens or in normal genomic DNA from patients with tumors harboring the SRC codon 531 mutation.


.0002   THROMBOCYTOPENIA 6 (1 family)

SRC, GLU527LYS
SNP: rs879255268, ClinVar: RCV000211002, RCV001003535

In affected members of a 3-generation family with thrombocytopenia-6 (THC6; 616937), Turro et al. (2016) identified a heterozygous c.1579G-A transition in the SRC gene, resulting in a glu527-to-lys (E527K) substitution at a conserved residue in the kinase domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the ExAC database or in 2,974 in-house control subjects. In vitro functional expression assays showed that the mutation resulted in high kinase activity compared to wildtype, consistent with a dominant gain of function. Immunoblot analysis of patient cells showed increased levels of active SRC and overall increased tyrosine phosphorylation compared to controls. Transfection of the mutation into control blood stem cells caused defective megakaryopoiesis associated with increased overall tyrosine phosphorylation in megakaryocytes. Compared with control conditions, more megakaryocytes were immature and had defects in proplatelet formation, with alterations in the actin cytoskeleton and podosome structures when adhered to fibrinogen. These abnormalities resembled those found in patient bone marrow biopsies and could be rescued using an SRC inhibitor. Expression of the mutation in zebrafish embryos resulted in abnormal early primitive hematopoiesis, thrombocytopenia, and smaller bones compared to controls.


See Also:

Czernilofsky et al. (1983); Gibbs et al. (1985); Sakaguchi et al. (1985); Sakaguchi et al. (1984)

REFERENCES

  1. Avizienyte, E., Wyke, A. W., Jones, R. J., McLean, G. W., Westhoff, M. A., Brunton, V. G., Frame, M. C. Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signalling. Nature Cell Biol. 4: 632-638, 2002. [PubMed: 12134161] [Full Text: https://doi.org/10.1038/ncb829]

  2. Azarnia, R., Reddy, S., Kmiecik, T. E., Shalloway, D., Loewenstein, W. R. The cellular src gene product regulates junctional cell-to-cell communication. Science 239: 398-401, 1988. [PubMed: 2447651] [Full Text: https://doi.org/10.1126/science.2447651]

  3. Czernilofsky, A. P., Levinson, A. D., Varmus, H. E., Bishop, J. M., Tischer, E., Goodman, H. Correction to the nucleotide sequence of the src gene of Rous sarcoma virus. Nature 301: 736-738, 1983. [PubMed: 6298633] [Full Text: https://doi.org/10.1038/301736b0]

  4. Gibbs, C. P., Tanaka, A., Anderson, S. K., Radul, J., Baar, J., Ridgway, A., Kung, H.-J., Fujita, D. J. Isolation and structural mapping of a human c-src gene homologous to the transforming gene (v-src) of Rous sarcoma virus. J. Virol. 53: 19-24, 1985. [PubMed: 2981336] [Full Text: https://doi.org/10.1128/JVI.53.1.19-24.1985]

  5. Irby, R. B., Mao, W., Coppola, D., Kang, J., Loubeau, J. M., Trudeau, W., Karl, R., Fujita, D. J., Jove, R., Yeatman, T. J. Activating SRC mutation in a subset of advanced human colon cancers. Nature Genet. 21: 187-190, 1999. [PubMed: 9988270] [Full Text: https://doi.org/10.1038/5971]

  6. Le Beau, M. M., Westbrook, C. A., Diaz, M. O., Rowley, J. D. Evidence for two distinct c-src loci on human chromosomes 1 and 20. Nature 312: 70-71, 1984. [PubMed: 6092965] [Full Text: https://doi.org/10.1038/312070a0]

  7. Le Beau, M. M., Westbrook, C. A., Diaz, M. O., Rowley, J. D. c-src is consistently conserved in the chromosomal deletion (20q) observed in myeloid disorders. Proc. Nat. Acad. Sci. 82: 6692-6696, 1985. [PubMed: 2413444] [Full Text: https://doi.org/10.1073/pnas.82.19.6692]

  8. Lebo, R. V., Cheung, M.-C., Bruce, B. D. Rapid gene mapping by dual laser chromosome sorting and spot blot DNA analysis. (Abstract) Am. J. Hum. Genet. 36: 101S, 1984.

  9. Lievens, P. M.-J., Kuznetsova, T., Kochlasmazashvili, G., Cesca, F., Gorinski, N., Galil, D. A., Cherkas, V., Ronkina, N., Lafera, J., Gaestel, M., Ponimaskin, E. ZDHHC3 tyrosine phosphorylation regulates neural cell adhesion molecule palmitoylation. Molec. Cell. Biol. 36: 2208-2225, 2016. [PubMed: 27247265] [Full Text: https://doi.org/10.1128/MCB.00144-16]

  10. Lowe, C., Yoneda, T., Boyce, B. F., Chen, H., Mundy, G. R., Soriano, P. Osteopetrosis in Src-deficient mice is due to an autonomous defect of osteoclasts. Proc. Nat. Acad. Sci. 90: 4485-4489, 1993. [PubMed: 7685105] [Full Text: https://doi.org/10.1073/pnas.90.10.4485]

  11. Luttrell, L. M., Ferguson, S. S. G., Daaka, Y., Miller, W. E., Maudsley, S., Della Rocca, G. J., Lin, F.-T., Kawakatsu, H., Owada, K., Luttrell, D. K., Caron, M. G., Lefkowitz, R. J. Beta-arrestin-dependent formation of beta-2 adrenergic receptor-Src protein kinase complexes. Science 283: 655-661, 1999. [PubMed: 9924018] [Full Text: https://doi.org/10.1126/science.283.5402.655]

  12. Morris, C. M., Honeybone, L. M., Hollings, P. E., Fitzgerald, P. H. Localization of the SRC oncogene to chromosome band 20q11.2 and loss of this gene with deletion (20q) in two leukemic patients. Blood 74: 1768-1773, 1989. [PubMed: 2506951]

  13. Parker, R. C., Mardon, G., Lebo, R. V., Varmus, H. E., Bishop, J. M. Isolation of duplicated human c-src genes located on chromosomes 1 and 20. Molec. Cell. Biol. 5: 831-838, 1985. [PubMed: 2581127] [Full Text: https://doi.org/10.1128/mcb.5.4.831-838.1985]

  14. Pitcher, G. M., Kalia, L. V., Ng, D., Goodfellow, N. M., Yee, K. T., Lambe, E. K., Salter, M. W. Schizophrenia susceptibility pathway neuregulin 1-ErbB4 suppresses Src upregulation of NMDA receptors. Nature Med. 17: 470-478, 2011. [PubMed: 21441918] [Full Text: https://doi.org/10.1038/nm.2315]

  15. Reinecke, J. B., Katafiasz, D., Naslavsky, N., Caplan, S. Regulation of Src trafficking and activation by the endocytic regulatory proteins MICAL-L1 and EHD1. J. Cell Sci. 127: 1684-1698, 2014. [PubMed: 24481818] [Full Text: https://doi.org/10.1242/jcs.133892]

  16. Sakaguchi, A. Y., Mohandas, T., Naylor, S. L. A human c-src gene resides on the proximal long arm of chromosome 20 (cen-q13.1). Cancer Genet. Cytogenet. 18: 123-129, 1985. [PubMed: 2996754] [Full Text: https://doi.org/10.1016/0165-4608(85)90062-7]

  17. Sakaguchi, A. Y., Naylor, S. L., Weinberg, R. A., Shows, T. B. Organization of human proto-oncogenes. (Abstract) Am. J. Hum. Genet. 34: 175A, 1982.

  18. Sakaguchi, A. Y., Zabel, B. U., Grzeschik, K. H., Law, M. L., Naylor, S. L. Human proto-oncogene assignments. (Abstract) Cytogenet. Cell Genet. 37: 572-573, 1984.

  19. Sandilands, E., Cans, C., Fincham, V. J., Brunton, V. G., Mellor, H., Prendergast, G. C., Norman, J. C., Superti-Furga, G., Frame, M. C. RhoB and actin polymerization coordinate Src activation with endosome-mediated delivery to the membrane. Dev. Cell 7: 855-869, 2004. [PubMed: 15572128] [Full Text: https://doi.org/10.1016/j.devcel.2004.09.019]

  20. Schinke, T., Schilling, A. F., Baranowsky, A., Seitz, S., Marshall, R. P., Linn, T., Blaeker, M., Huebner, A. K., Schulz, A., Simon, R., Gebauer, M., Priemel, M., and 15 others. Impaired gastric acidification negatively affects calcium homeostasis and bone mass. Nature Med. 15: 674-681, 2009. [PubMed: 19448635] [Full Text: https://doi.org/10.1038/nm.1963]

  21. Soriano, P., Montgomery, C., Geske, R., Bradley, A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64: 693-702, 1991. [PubMed: 1997203] [Full Text: https://doi.org/10.1016/0092-8674(91)90499-o]

  22. Taniguchi, K., Wu, L.-W., Grivennikov, S. I., de Jong, P. R., Lian, I., Yu, F.-X., Wang, K., Ho, S. B., Boland, B. S., Chang, J. T., Sandborn, W. J., Hardiman, G., Raz, E., Maehara, Y., Yoshimura, A., Zucman-Rossi, J., Guan, K.-L., Karin, M. A gp130-Src-YAP module links inflammation to epithelial regeneration. Nature 519: 57-62, 2015. [PubMed: 25731159] [Full Text: https://doi.org/10.1038/nature14228]

  23. Turro, E., Greene, D., Wijgaerts, A., Thys, C., Lentaigne, C., Bariana, T. K., Westbury, S. J., Kelly, A. M., Selleslag, D., Stephens, J. C., Papadia, S., Simeoni, I., and 32 others. A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies. Sci. Transl. Med. 8: 328ra30, 2016. Note: Electronic Article. [PubMed: 26936507] [Full Text: https://doi.org/10.1126/scitranslmed.aad7666]

  24. Wong, B. R., Besser, D., Kim, N., Arron, J. R., Vologodskaia, M., Hanafusa, H., Choi, Y. TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Molec. Cell 4: 1041-1049, 1999. [PubMed: 10635328] [Full Text: https://doi.org/10.1016/s1097-2765(00)80232-4]

  25. Xing, L., Venegas, A. M., Chen, A., Garrett-Beal, L., Boyce, B. F., Varmus, H. E., Schwartzberg, P. L. Genetic evidence for a role for Src family kinases in TNF family receptor signaling and cell survival. Genes Dev. 15: 241-253, 2001. [PubMed: 11157779] [Full Text: https://doi.org/10.1101/gad.840301]

  26. Yeung, T., Terebiznik, M., Yu, L., Silvius, J., Abidi, W. M., Philips, M., Levine, T., Kapus, A., Grinstein, S. Receptor activation alters inner surface potential during phagocytosis. Science 313: 347-351, 2006. [PubMed: 16857939] [Full Text: https://doi.org/10.1126/science.1129551]

  27. Yu, X.-M., Askalan, R., Keil, G. J, II, Salter, M. W. NMDA channel regulation by channel-associated protein tyrosine kinase Src. Science 275: 674-678, 1997. [PubMed: 9005855] [Full Text: https://doi.org/10.1126/science.275.5300.674]


Contributors:
Bao Lige - updated : 10/12/2021
Patricia A. Hartz - updated : 10/07/2016
Cassandra L. Kniffin - updated : 5/3/2016
Ada Hamosh - updated : 6/3/2015
Cassandra L. Kniffin - updated : 9/6/2011
Marla J. F. O'Neill - updated : 8/4/2009
Ada Hamosh - updated : 11/28/2006
Patricia A. Hartz - updated : 1/6/2005
Patricia A. Hartz - updated : 12/17/2002
Stylianos E. Antonarakis - updated : 1/7/2000
Ada Hamosh - updated : 2/1/1999
Victor A. McKusick - updated : 1/28/1999

Creation Date:
Victor A. McKusick : 6/2/1986

Edit History:
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ckniffin : 5/3/2016
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joanna : 6/22/2014
carol : 9/7/2011
ckniffin : 9/6/2011
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psherman : 6/6/1998
mark : 3/18/1996
carol : 11/22/1993
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supermim : 3/16/1992
carol : 2/24/1992
carol : 3/12/1991
supermim : 3/20/1990