Disease relevance of Cttn

• Cortactin-depleted osteoclasts displayed a complete loss of bone resorption with no formation of sealing zones [1].
• Cooperative roles of Fyn and cortactin in cell migration of metastatic murine melanoma [2].
• A MAb specific for cortactin, a filamentous-actin binding pp60src substrate, immunoprecipitated proteins from murine plasma-cytoma cell lines but not from pre-B cell lymphoma or B cell lymphoma cell lines [3].
• We mimicked 11q13 amplification by generating MMTV-cortactin/-MMTV-cyclin D1 bitransgenic mice but did not observe any synergistic effect of cortactin on cyclin D1-induced mammary hyperplasias or carcinomas, nor development of distant metastasis [4].
• To study the role of cortactin in mammary gland tumorigenesis, we examined mouse mammary tumor virus (MMTV)-cortactin transgenic mice and MMTV-cortactin/-MMTV-cyclin D1 bitransgenic mice [4].

High impact information on Cttn

• Cortactin, a p80-85 substrate of src- and fyn-related kinases that localizes with actin at cell adhesion sites, is increasingly tyrosine phosphorylated in calcium- and TPA-induced differentiation, with a time course which parallels that of fyn activation [5].
• HS1, the leukocyte-specific homolog of cortactin, regulates F-actin in vitro and is phosphorylated in response to TCR ligation, but its role in lymphocyte activation has not been addressed [6].
• Cortactin, a filamentous actin (F-actin)-associated protein and prominent substrate of Src, is implicated in progression of breast tumours through gene amplification at chromosome 11q13 [7].
• When ligated by heparin-binding (HB) growth-associated molecule (GAM; pleiotrophin), N-syndecan mediates cortactin-Src kinase-dependent neurite outgrowth [8].
• Furthermore, Y-->D mutation of three tyrosine residues targeted by Src (Y421, Y466, and Y482) inhibited the ability of S405,418D cortactin to activate N-WASP [9].

Chemical compound and disease context of Cttn

• Overexpression as well as tyrosine phosphorylation of cortactin has been reported to enhance cell migration, invasion, and metastasis [10].

Biological context of Cttn

• To address the role of cortactin and actin assembly in osteoclasts, we depleted cortactin by RNA interference [1].
• In this report, we identify a role for the cortactin C-terminus in regulating cell migration and, more specifically, actin dynamics [11].
• These data suggest an important role of cortactin in Sertoli cell-spermatid interactions and in the Dspd phenotype [12].
• Cortactin tyrosine phosphorylation is progressive, with tyrosine 421 phosphorylation required for phosphorylation of tyrosine 466 [13].
• Collectively these data provide evidence for cortactin as a putative target of Rac1-induced signal transduction events involved in membrane ruffling and lamellipodia formation [14].

Anatomical context of Cttn

• Cortactin has an essential and specific role in osteoclast actin assembly [1].
• Overexpression of either full-length cortactin or cortactin C-terminus is sufficient to enhance migration of mammary epithelial cells [11].
• Immunohistochemical analysis revealed localization of cortactin beside elongated spermatids in wild-type testes; abnormality of cortactin localization was found in mutant testes [12].
• Cortactin tyrosine phosphorylation requires Rac1 activity and association with the cortical actin cytoskeleton [13].
• Hyperosmotic cortactin phosphorylation was reduced in Fyn-deficient fibroblasts but remained intact in Src-deficient fibroblasts [15].

Associations of Cttn with chemical compounds

• In contrast, expression of a cortactin mutant lacking tyrosine residues phosphorylated by Src did not restore podosome formation [1].
• In contrast, deletion of an MIM proline-rich domain, which is required for an optimal binding to cortactin, substantiated the MIM-mediated inhibition of cell motility [16].
• Estrogen agonists, 17beta-estradiol, bisphenol A, and diethylstilbestrol, decrease cortactin expression in the mouse testis [17].
• Both integrin-mediated Fyn activation and hyperphosphorylation of cortactin were observed 2-5 h after stimulation in highly metastatic cells, and they required de novo protein synthesis [2].
• Flutamide depresses expression of cortactin in the ectoplasmic specialization between the Sertoli cells and spermatids in the mouse testis [18].
• Even though cortactin can be tyrosine phosphorylated by Src-family kinases in vitro [8], we show that Abl and Arg are more adept at binding and phosphorylating cortactin [19].
• Also inhibited is the separation of centrosomes when a truncated form of cortactin is expressed, whose C-terminus contains the tyrosine phosphorylation region but lacks the actin-binding domains [20].

Physical interactions of Cttn

• Galpha13 stimulates cell migration through cortactin-interacting protein Hax-1 [21].

Regulatory relationships of Cttn

• These results indicate that cortactin tyrosine phosphorylation requires Rac1-induced cortactin targeting to cortical actin networks, where it is tyrosine phosphorylated in hierarchical manner that is closely coordinated with its ability to regulate actin dynamics [13].
• Cell shrinkage regulates Src kinases and induces tyrosine phosphorylation of cortactin, independent of the osmotic regulation of Na+/H+ exchangers [15].
• The tyrosine phosphorylation of cortactin induced by FGF-1 requires the tyrosine residues 421, 482 and 466, which are targeted by the protein tyrosine kinase Src in vitro [22].

Other interactions of Cttn

• Cortactin, a c-Src substrate known to promote Arp2/3-mediated actin assembly in vitro, is expressed in osteoclasts and localizes to the sealing ring [1].
• Cortactin was found to be an early component of the nascent podosome belt, along with dynamin, supporting a role for cortactin in actin assembly [1].
• Cttn encodes the actin-binding protein cortactin [12].
• Translocation of cortactin to the cell periphery is mediated by the small GTPase Rac1 [14].
• Therefore, Fer likely serves a redundant role in regulating cell growth, cell adhesion, retinal development, and spermatogenesis but is required for efficient phosphorylation of cortactin [23].

Analytical, diagnostic and therapeutic context of Cttn

• Mice testes were observed for the expression of cortactin protein after E2, BPA, and DES treatments by Western blot analysis, immunohistochemical analysis, and immunoelectron microscopic analysis [17].
• Immunohistochemistry and immunoelectron microscopy showed that FLUT depressed cortactin expression in the apical ES [18].
• Fgd1 and cortactin may participate as scaffolds and signal transducers in a positive feedback cycle to promote actin assembly at the cell cortex [24].
• We show here that cortactin can promote sedimentation of F-actin at centrifugation forces under which F-actin is otherwise not able to be precipitated [25].
• Electron microscopic analysis after negative staining further revealed that actin filaments in the presence of cortactin are cross-linked into bundles of various degrees of thickness [25].

References