* 164765

CORTACTIN; CTTN


Alternative titles; symbols

ONCOGENE EMS1; EMS1


HGNC Approved Gene Symbol: CTTN

Cytogenetic location: 11q13.3     Genomic coordinates (GRCh38): 11:70,398,529-70,436,575 (from NCBI)


TEXT

Description

Cortactin is a multidomain protein that functions as a key regulator of the actin cytoskeleton. It has roles in many actin-based cellular processes, including cell migration and invasion, tumor cell metastasis, and endocytosis (summary by Tegtmeyer et al., 2011).


Cloning and Expression

Amplification of the 11q13 region is frequently found in breast cancer and in squamous cell carcinomas of the head and neck. The known oncogenes within the amplified 11q13 region, INT2 (164950) and FGF4 (164980), are rarely expressed in these tumors, indicating that another, hitherto unidentified gene or genes are involved in the unfavorable clinical course of disease associated with such amplification. To identify the gene or genes, Schuuring et al. (1992) constructed a cDNA library from a cell line with an 11q13 amplification and performed a differential cDNA cloning using labeled cDNAs from human squamous cell carcinoma cell lines with and without an 11q13 amplification. They isolated 2 cDNA clones, U21B31 and U21C8, which recognized genes amplified and overexpressed in cell lines harboring an 11q13 amplification. Sequence analysis of the U21C8 cDNA clone revealed no homology to known genes; they called this gene EMS1. The U21B31 cDNA clone corresponded to the 3-prime end of the PRAD1 protooncogene (168461).

Van Damme et al. (1997) stated that EMS1 is the human homolog of chicken cortactin, an actin-binding protein involved in the restructuring of the cortical actin cytoskeleton. Chicken cortactin is a substrate for the pp60v-src tyrosine kinase (see 190090).


Gene Function

Human cortactin is overexpressed in carcinoma cells with an amplification of 11q13 and is found in 2 forms, designated p80 and p85. Van Damme et al. (1997) found that in carcinoma cells with the 11q13 amplification, p85 was produced from p80 by posttranslational modification. Also, treatment of these cells with epidermal growth factor (131530) or vanadate caused conversion of p80 to p85 and enhanced phosphorylation of the p85 form. Both overexpression and posttranslational modification of cortactin coincided with its redistribution from the cytoplasm to cell-matrix contact sites, implying a role for cortactin in the modulation of cellular adhesive properties.

Williams et al. (2007) stated that suppression of Kv1.2 (KCNA2; 176262)-mediated potassium channel currents occurs by endocytosis of the channel protein following its tyrosine phosphorylation. Using pull-down assays with purified recombinant proteins, they had previously demonstrated direct interaction between Kv1.2 and cortactin that was reduced by tyrosine phosphorylation of Kv1.2 (Hattan et al., 2002). Using cells and cDNAs from several species, including human, Williams et al. (2007) showed that cortactin interacted with Kv1.2 in vivo and was required for Kv1.2 membrane localization and channel function. Depletion of endogenous cortactin in HEK293 cells via RNA interference reduced surface Kv1.2 levels, which could be restored by introduction of mouse cortactin. Kv1.2 trafficking required the cortactin actin regulatory domains and was modulated by phosphorylation of cortactin C-terminal tyrosines. Williams et al. (2007) concluded that cortactin-mediated actin remodeling in excitable cells has a direct impact on membrane excitability.

Tegtmeyer et al. (2011) found that knockdown of CTTN via small interfering RNA in a human gastric adenocarcinoma cell line inhibited cell scattering and elongation induced by infection with Helicobacter pylori (Hp). Hp-induced scattering and elongation correlated with activation of PAK1 (602590) and ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) and inactivation of SRC (190090). Phospho-specific antibodies to CTTN serine residues showed phosphorylation and membrane expression after Hp infection, while tyrosine residues of CTTN were dephosphorylated. Ser418 and ser405 residues were specifically phosphorylated in p80 and p85, respectively. Hp-induced serine phosphorylation in CTTN was independent of the Hp cytotoxin-associated gene A (CagA) effector protein, whereas tyrosine dephosphorylation in CTTN was dependent on CagA. Immunoprecipitation analysis detected interaction of CTTN with N-WASP (WASL; 605056) and actin only in uninfected cells. Immunofluorescence analysis of uninfected cells demonstrated localization of CTTN in cytoplasm and membrane, which shifted after Hp infection to colocalization with FAK (PTK2; 600758) at the tip and base of cellular elongations. Interaction of CTTN with FAK required phosphorylation of either ser405 or ser418, but not both simultaneously, and involved binding of the CTTN SH3 domain with a PxxP motif, designated PR3, of FAK. Binding of CTTN phosphorylated at ser405, but not CTTN phosphorylated at ser418, to FAK increased FAK kinase activity. Tegtmeyer et al. (2011) proposed that Hp targets cortactin to protect the gastric epithelium from excessive cell lifting and to ensure sustained infection in the stomach.


Mapping

Gross (2012) mapped the CTTN gene to chromosome 11q13.3 based on an alignment of the CTTN sequence (GenBank BC008799) with the genomic sequence (GRCh37).


REFERENCES

  1. Gross, M. B. Personal Communication. Baltimore, Md. 3/21/2012.

  2. Hattan, D., Nesti, E., Cachero, T. G., Morielli, A. D. Tyrosine phosphorylation of Kv1.2 modulates its interaction with the actin-binding protein cortactin. J. Biol. Chem. 277: 38596-38606, 2002. [PubMed: 12151401, related citations] [Full Text]

  3. Schuuring, E., Verhoeven, E., Mooi, W. J., Michalides, R. J. A. M. Identification and cloning of two overexpressed genes, U21B31/PRAD1 and EMS1, within the amplified chromosome 11q13 region in human carcinomas. Oncogene 7: 355-361, 1992. [PubMed: 1532244, related citations]

  4. Tegtmeyer, N., Wittelsberger, R., Hartig, R., Wessler, S., Martinez-Quiles, N., Backert, S. Serine phosphorylation of cortactin controls focal adhesion kinase activity and cell scattering induced by Helicobacter pylori. Cell Host Microbe 9: 520-531, 2011. [PubMed: 21669400, related citations] [Full Text]

  5. van Damme, H., Brok, H., Schuuring-Scholtes, E., Schuuring, E. The redistribution of cortactin into cell-matrix contact sites in human carcinoma cells with 11q13 amplification is associated with both overexpression and post-translational modification. J. Biol. Chem. 272: 7374-7380, 1997. [PubMed: 9054437, related citations] [Full Text]

  6. Williams, M. R., Markey, J. C., Doczi, M. A., Morielli, A. D. An essential role for cortactin in the modulation of the potassium channel Kv1.2. Proc. Nat. Acad. Sci. 104: 17412-17417, 2007. [PubMed: 17959782, images, related citations] [Full Text]


Matthew B. Gross - updated : 03/21/2012
Paul J. Converse - updated : 3/15/2012
Patricia A. Hartz - updated : 8/20/2008
Jennifer P. Macke - updated : 11/16/1998
Creation Date:
Victor A. McKusick : 5/27/1993
mgross : 03/21/2012
terry : 3/15/2012
mgross : 8/21/2008
terry : 8/20/2008
alopez : 11/16/1998
alopez : 11/16/1998
terry : 8/11/1998
carol : 5/28/1993
carol : 5/27/1993

* 164765

CORTACTIN; CTTN


Alternative titles; symbols

ONCOGENE EMS1; EMS1


HGNC Approved Gene Symbol: CTTN

Cytogenetic location: 11q13.3     Genomic coordinates (GRCh38): 11:70,398,529-70,436,575 (from NCBI)


TEXT

Description

Cortactin is a multidomain protein that functions as a key regulator of the actin cytoskeleton. It has roles in many actin-based cellular processes, including cell migration and invasion, tumor cell metastasis, and endocytosis (summary by Tegtmeyer et al., 2011).


Cloning and Expression

Amplification of the 11q13 region is frequently found in breast cancer and in squamous cell carcinomas of the head and neck. The known oncogenes within the amplified 11q13 region, INT2 (164950) and FGF4 (164980), are rarely expressed in these tumors, indicating that another, hitherto unidentified gene or genes are involved in the unfavorable clinical course of disease associated with such amplification. To identify the gene or genes, Schuuring et al. (1992) constructed a cDNA library from a cell line with an 11q13 amplification and performed a differential cDNA cloning using labeled cDNAs from human squamous cell carcinoma cell lines with and without an 11q13 amplification. They isolated 2 cDNA clones, U21B31 and U21C8, which recognized genes amplified and overexpressed in cell lines harboring an 11q13 amplification. Sequence analysis of the U21C8 cDNA clone revealed no homology to known genes; they called this gene EMS1. The U21B31 cDNA clone corresponded to the 3-prime end of the PRAD1 protooncogene (168461).

Van Damme et al. (1997) stated that EMS1 is the human homolog of chicken cortactin, an actin-binding protein involved in the restructuring of the cortical actin cytoskeleton. Chicken cortactin is a substrate for the pp60v-src tyrosine kinase (see 190090).


Gene Function

Human cortactin is overexpressed in carcinoma cells with an amplification of 11q13 and is found in 2 forms, designated p80 and p85. Van Damme et al. (1997) found that in carcinoma cells with the 11q13 amplification, p85 was produced from p80 by posttranslational modification. Also, treatment of these cells with epidermal growth factor (131530) or vanadate caused conversion of p80 to p85 and enhanced phosphorylation of the p85 form. Both overexpression and posttranslational modification of cortactin coincided with its redistribution from the cytoplasm to cell-matrix contact sites, implying a role for cortactin in the modulation of cellular adhesive properties.

Williams et al. (2007) stated that suppression of Kv1.2 (KCNA2; 176262)-mediated potassium channel currents occurs by endocytosis of the channel protein following its tyrosine phosphorylation. Using pull-down assays with purified recombinant proteins, they had previously demonstrated direct interaction between Kv1.2 and cortactin that was reduced by tyrosine phosphorylation of Kv1.2 (Hattan et al., 2002). Using cells and cDNAs from several species, including human, Williams et al. (2007) showed that cortactin interacted with Kv1.2 in vivo and was required for Kv1.2 membrane localization and channel function. Depletion of endogenous cortactin in HEK293 cells via RNA interference reduced surface Kv1.2 levels, which could be restored by introduction of mouse cortactin. Kv1.2 trafficking required the cortactin actin regulatory domains and was modulated by phosphorylation of cortactin C-terminal tyrosines. Williams et al. (2007) concluded that cortactin-mediated actin remodeling in excitable cells has a direct impact on membrane excitability.

Tegtmeyer et al. (2011) found that knockdown of CTTN via small interfering RNA in a human gastric adenocarcinoma cell line inhibited cell scattering and elongation induced by infection with Helicobacter pylori (Hp). Hp-induced scattering and elongation correlated with activation of PAK1 (602590) and ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) and inactivation of SRC (190090). Phospho-specific antibodies to CTTN serine residues showed phosphorylation and membrane expression after Hp infection, while tyrosine residues of CTTN were dephosphorylated. Ser418 and ser405 residues were specifically phosphorylated in p80 and p85, respectively. Hp-induced serine phosphorylation in CTTN was independent of the Hp cytotoxin-associated gene A (CagA) effector protein, whereas tyrosine dephosphorylation in CTTN was dependent on CagA. Immunoprecipitation analysis detected interaction of CTTN with N-WASP (WASL; 605056) and actin only in uninfected cells. Immunofluorescence analysis of uninfected cells demonstrated localization of CTTN in cytoplasm and membrane, which shifted after Hp infection to colocalization with FAK (PTK2; 600758) at the tip and base of cellular elongations. Interaction of CTTN with FAK required phosphorylation of either ser405 or ser418, but not both simultaneously, and involved binding of the CTTN SH3 domain with a PxxP motif, designated PR3, of FAK. Binding of CTTN phosphorylated at ser405, but not CTTN phosphorylated at ser418, to FAK increased FAK kinase activity. Tegtmeyer et al. (2011) proposed that Hp targets cortactin to protect the gastric epithelium from excessive cell lifting and to ensure sustained infection in the stomach.


Mapping

Gross (2012) mapped the CTTN gene to chromosome 11q13.3 based on an alignment of the CTTN sequence (GenBank BC008799) with the genomic sequence (GRCh37).


REFERENCES

  1. Gross, M. B. Personal Communication. Baltimore, Md. 3/21/2012.

  2. Hattan, D., Nesti, E., Cachero, T. G., Morielli, A. D. Tyrosine phosphorylation of Kv1.2 modulates its interaction with the actin-binding protein cortactin. J. Biol. Chem. 277: 38596-38606, 2002. [PubMed: 12151401] [Full Text: https://doi.org/10.1074/jbc.M205005200]

  3. Schuuring, E., Verhoeven, E., Mooi, W. J., Michalides, R. J. A. M. Identification and cloning of two overexpressed genes, U21B31/PRAD1 and EMS1, within the amplified chromosome 11q13 region in human carcinomas. Oncogene 7: 355-361, 1992. [PubMed: 1532244]

  4. Tegtmeyer, N., Wittelsberger, R., Hartig, R., Wessler, S., Martinez-Quiles, N., Backert, S. Serine phosphorylation of cortactin controls focal adhesion kinase activity and cell scattering induced by Helicobacter pylori. Cell Host Microbe 9: 520-531, 2011. [PubMed: 21669400] [Full Text: https://doi.org/10.1016/j.chom.2011.05.007]

  5. van Damme, H., Brok, H., Schuuring-Scholtes, E., Schuuring, E. The redistribution of cortactin into cell-matrix contact sites in human carcinoma cells with 11q13 amplification is associated with both overexpression and post-translational modification. J. Biol. Chem. 272: 7374-7380, 1997. [PubMed: 9054437] [Full Text: https://doi.org/10.1074/jbc.272.11.7374]

  6. Williams, M. R., Markey, J. C., Doczi, M. A., Morielli, A. D. An essential role for cortactin in the modulation of the potassium channel Kv1.2. Proc. Nat. Acad. Sci. 104: 17412-17417, 2007. [PubMed: 17959782] [Full Text: https://doi.org/10.1073/pnas.0703865104]


Contributors:
Matthew B. Gross - updated : 03/21/2012
Paul J. Converse - updated : 3/15/2012
Patricia A. Hartz - updated : 8/20/2008
Jennifer P. Macke - updated : 11/16/1998

Creation Date:
Victor A. McKusick : 5/27/1993

Edit History:
mgross : 03/21/2012
terry : 3/15/2012
mgross : 8/21/2008
terry : 8/20/2008
alopez : 11/16/1998
alopez : 11/16/1998
terry : 8/11/1998
carol : 5/28/1993
carol : 5/27/1993