* 124095

C-TERMINAL SRC KINASE; CSK


Alternative titles; symbols

CYTOPLASMIC TYROSINE KINASE
c-SRC TYROSINE KINASE


HGNC Approved Gene Symbol: CSK

Cytogenetic location: 15q24.1     Genomic coordinates (GRCh38): 15:74,782,080-74,803,197 (from NCBI)


TEXT

Cloning and Expression

Partanen et al. (1991) cloned a novel cytoplasmic tyrosine kinase designated CSK. The CSK gene was ubiquitously expressed in human tissues as 2 mRNA species of 2.6 and 3.4 kb, although in some tissues and cell lines, only the larger mRNA was detected.


Gene Function

CSK downregulates tyrosine kinase activity of the SRC oncoprotein (190090) through tyrosine phosphorylation of the SRC carboxy terminus. Since cell transformation by SRC oncoproteins is caused by various mechanisms that interfere with this phosphorylation, the CSK gene might function as an antioncogene (Armstrong et al., 1992).

Cloutier and Veillette (1996) used the yeast 2-hybrid system to identify proteins associated with CSK. They found that the Src homology-3 (SH3) domain of CSK associates with a proline-rich region of PEP (600716), a protein-tyrosine phosphatase expressed in hemopoietic cells. Cloutier and Veillette (1996) showed that this association is highly specific and speculated that PEP may be an effector and/or regulator of CSK in T cells and other hemopoietic cells.


Mapping

Armstrong et al. (1992) used in situ hybridization to map the CSK gene to 15q23-q25.


Molecular Genetics

Associations Pending Confirmation

CSK physically interacts with the intracellular phosphatase LYP (PTPN22; 600716) and can modify the activation state of downstream Src kinases, such as LYN (165120), in lymphocytes. Manjarrez-Orduno et al. (2012) identified an association of CSK with systemic lupus erythematosus (SLE; 152700) and refined its location to the intronic polymorphism rs34933034 (odds ratio = 1.32; p = 1.04 x 10(-9)). The risk allele at this SNP is associated with increased CSK expression and augments inhibitory phosphorylation of LYN. In carriers of the risk allele, there is increased B-cell receptor-mediated activation of mature B cells, as well as higher concentrations of plasma IgM, relative to individuals in the nonrisk haplotype. Moreover, the fraction of transitional B cells is doubled in the cord blood of carriers of the risk allele, due to an expansion of late transitional cells in a stage targeted by selection mechanisms. Manjarrez-Orduno et al. (2012) concluded that their results suggested that the LYP-CSK complex increases susceptibility to lupus at multiple maturation and activation points in B cells.


Animal Model

Lowry et al. (2002) found that actin stress fiber formation induced by G proteins and G protein receptors was completely blocked in Csk-deficient mouse embryonic fibroblasts. Reintroduction of Csk into Csk-deficient cells restored G protein-induced actin stress fiber formation. Rescue experiments with catalytic mutants of Csk demonstrated that Csk catalytic activity was required for stress fiber formation. Lowry et al. (2002) found that G-beta (see GNB1; 139380)/G-gamma (see GNG2; 606981) dimers translocated Csk to the plasma membrane and directly increased Csk kinase activity. They concluded that CSK plays a critical role in mediating G protein signals in the reorganization of the actin cytoskeleton.


REFERENCES

  1. Armstrong, E., Cannizzaro, L., Bergman, M., Huebner, K., Alitalo, K. The c-src tyrosine kinase (CSK) gene, a potential antioncogene, localizes to human chromosome region 15q23-q25. Cytogenet. Cell Genet. 60: 119-120, 1992. [PubMed: 1377109, related citations] [Full Text]

  2. Cloutier, J.-F., Veillette, A. Association of inhibitory tyrosine protein kinase p50(csk) with protein tyrosine phosphatase PEP in T cells and other hemopoietic cells. EMBO J. 15: 4909-4918, 1996. [PubMed: 8890164, related citations]

  3. Lowry, W. E., Huang, J., Ma, Y.-C., Ali, S., Wang, D., Williams, D. M., Okada, M., Cole, P. A., Huang, X.-Y. Csk, a critical link of G protein signals to actin cytoskeletal reorganization. Dev. Cell 2: 733-744, 2002. [PubMed: 12062086, related citations] [Full Text]

  4. Manjarrez-Orduno, N., Marasco, E., Chung, S. A., Katz, M. S., Kiridly, J. F., Simpfendorfer, K. R., Freudenberg, J., Ballard, D. H., Nashi, E., Hopkins, T. J., Cunninghame Graham, D. S., Lee, A. T., and 11 others. CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation. Nature Genet. 44: 1227-1230, 2012. [PubMed: 23042117, images, related citations] [Full Text]

  5. Partanen, J., Armstrong, E., Bergman, M., Makela, T. P., Hirvonen, H., Huebner, K., Alitalo, K. Cyl encodes a putative cytoplasmic tyrosine kinase lacking the conserved tyrosine autophosphorylation site (Y416-src). Oncogene 6: 2013-2018, 1991. [PubMed: 1945408, related citations]


Ada Hamosh - updated : 1/11/2013
Patricia A. Hartz - updated : 9/8/2005
Jennifer P. Macke - updated : 11/20/1997
Creation Date:
Victor A. McKusick : 8/14/1992
carol : 01/28/2021
alopez : 01/15/2013
terry : 1/11/2013
mgross : 9/8/2005
alopez : 2/1/1999
alopez : 12/17/1997
alopez : 12/11/1997
alopez : 12/11/1997
carol : 8/17/1992
carol : 8/14/1992

* 124095

C-TERMINAL SRC KINASE; CSK


Alternative titles; symbols

CYTOPLASMIC TYROSINE KINASE
c-SRC TYROSINE KINASE


HGNC Approved Gene Symbol: CSK

Cytogenetic location: 15q24.1     Genomic coordinates (GRCh38): 15:74,782,080-74,803,197 (from NCBI)


TEXT

Cloning and Expression

Partanen et al. (1991) cloned a novel cytoplasmic tyrosine kinase designated CSK. The CSK gene was ubiquitously expressed in human tissues as 2 mRNA species of 2.6 and 3.4 kb, although in some tissues and cell lines, only the larger mRNA was detected.


Gene Function

CSK downregulates tyrosine kinase activity of the SRC oncoprotein (190090) through tyrosine phosphorylation of the SRC carboxy terminus. Since cell transformation by SRC oncoproteins is caused by various mechanisms that interfere with this phosphorylation, the CSK gene might function as an antioncogene (Armstrong et al., 1992).

Cloutier and Veillette (1996) used the yeast 2-hybrid system to identify proteins associated with CSK. They found that the Src homology-3 (SH3) domain of CSK associates with a proline-rich region of PEP (600716), a protein-tyrosine phosphatase expressed in hemopoietic cells. Cloutier and Veillette (1996) showed that this association is highly specific and speculated that PEP may be an effector and/or regulator of CSK in T cells and other hemopoietic cells.


Mapping

Armstrong et al. (1992) used in situ hybridization to map the CSK gene to 15q23-q25.


Molecular Genetics

Associations Pending Confirmation

CSK physically interacts with the intracellular phosphatase LYP (PTPN22; 600716) and can modify the activation state of downstream Src kinases, such as LYN (165120), in lymphocytes. Manjarrez-Orduno et al. (2012) identified an association of CSK with systemic lupus erythematosus (SLE; 152700) and refined its location to the intronic polymorphism rs34933034 (odds ratio = 1.32; p = 1.04 x 10(-9)). The risk allele at this SNP is associated with increased CSK expression and augments inhibitory phosphorylation of LYN. In carriers of the risk allele, there is increased B-cell receptor-mediated activation of mature B cells, as well as higher concentrations of plasma IgM, relative to individuals in the nonrisk haplotype. Moreover, the fraction of transitional B cells is doubled in the cord blood of carriers of the risk allele, due to an expansion of late transitional cells in a stage targeted by selection mechanisms. Manjarrez-Orduno et al. (2012) concluded that their results suggested that the LYP-CSK complex increases susceptibility to lupus at multiple maturation and activation points in B cells.


Animal Model

Lowry et al. (2002) found that actin stress fiber formation induced by G proteins and G protein receptors was completely blocked in Csk-deficient mouse embryonic fibroblasts. Reintroduction of Csk into Csk-deficient cells restored G protein-induced actin stress fiber formation. Rescue experiments with catalytic mutants of Csk demonstrated that Csk catalytic activity was required for stress fiber formation. Lowry et al. (2002) found that G-beta (see GNB1; 139380)/G-gamma (see GNG2; 606981) dimers translocated Csk to the plasma membrane and directly increased Csk kinase activity. They concluded that CSK plays a critical role in mediating G protein signals in the reorganization of the actin cytoskeleton.


REFERENCES

  1. Armstrong, E., Cannizzaro, L., Bergman, M., Huebner, K., Alitalo, K. The c-src tyrosine kinase (CSK) gene, a potential antioncogene, localizes to human chromosome region 15q23-q25. Cytogenet. Cell Genet. 60: 119-120, 1992. [PubMed: 1377109] [Full Text: https://doi.org/10.1159/000133318]

  2. Cloutier, J.-F., Veillette, A. Association of inhibitory tyrosine protein kinase p50(csk) with protein tyrosine phosphatase PEP in T cells and other hemopoietic cells. EMBO J. 15: 4909-4918, 1996. [PubMed: 8890164]

  3. Lowry, W. E., Huang, J., Ma, Y.-C., Ali, S., Wang, D., Williams, D. M., Okada, M., Cole, P. A., Huang, X.-Y. Csk, a critical link of G protein signals to actin cytoskeletal reorganization. Dev. Cell 2: 733-744, 2002. [PubMed: 12062086] [Full Text: https://doi.org/10.1016/s1534-5807(02)00175-2]

  4. Manjarrez-Orduno, N., Marasco, E., Chung, S. A., Katz, M. S., Kiridly, J. F., Simpfendorfer, K. R., Freudenberg, J., Ballard, D. H., Nashi, E., Hopkins, T. J., Cunninghame Graham, D. S., Lee, A. T., and 11 others. CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation. Nature Genet. 44: 1227-1230, 2012. [PubMed: 23042117] [Full Text: https://doi.org/10.1038/ng.2439]

  5. Partanen, J., Armstrong, E., Bergman, M., Makela, T. P., Hirvonen, H., Huebner, K., Alitalo, K. Cyl encodes a putative cytoplasmic tyrosine kinase lacking the conserved tyrosine autophosphorylation site (Y416-src). Oncogene 6: 2013-2018, 1991. [PubMed: 1945408]


Contributors:
Ada Hamosh - updated : 1/11/2013
Patricia A. Hartz - updated : 9/8/2005
Jennifer P. Macke - updated : 11/20/1997

Creation Date:
Victor A. McKusick : 8/14/1992

Edit History:
carol : 01/28/2021
alopez : 01/15/2013
terry : 1/11/2013
mgross : 9/8/2005
alopez : 2/1/1999
alopez : 12/17/1997
alopez : 12/11/1997
alopez : 12/11/1997
carol : 8/17/1992
carol : 8/14/1992