Specific Oncogenic Activity of the Src-Family Tyrosine Kinase c-Yes in Colon Carcinoma Cells

Sancier, Florence; Dumont, Aurélie; Sirvent, Audrey; Plater, Ludmilla Paquay de; Edmonds, Thomas; David, Géraldine; Jan, Michel; Montrion, Catherine de; Cogé, Francis; Léonce, Stéphane; Burbridge, Michael; Bruno, Alain; Boutin, Jean A.; Lockhart, Brian P.; Roche, Serge; Cruzalegui, Francisco

doi:10.1371/journal.pone.0017237

Cited by 37 publications

(40 citation statements)

References 25 publications

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“…Although c-Src and its closest phylogenetic relative, c-Yes, are co-expressed in this cell type, c-Src activity drives ES cell differentiation while c-Yes suppresses differentiation and drives self-renewal [16]–[18]. Along similar lines, RNAi-mediated knock-down of c-Yes expression in colon cancer cell lines increased apoptosis and reduced cell migration and tumor growth, while c-Src knock-down yielded a much less dramatic effect on the same phenotypes, suggestive of a dominant role for c-Yes vs. c-Src in colon cancer [19]. These differences in individual functions raise fundamental questions about what mechanisms selectively regulate specific family members, especially in cellular contexts where multiple SFKs are co-expressed.…”

Section: Introductionmentioning

confidence: 80%

Differential Sensitivity of Src-Family Kinases to Activation by SH3 Domain Displacement

et al. 2014

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Src-family kinases (SFKs) are non-receptor protein-tyrosine kinases involved in a variety of signaling pathways in virtually every cell type. The SFKs share a common negative regulatory mechanism that involves intramolecular interactions of the SH3 domain with the PPII helix formed by the SH2-kinase linker as well as the SH2 domain with a conserved phosphotyrosine residue in the C-terminal tail. Growing evidence suggests that individual SFKs may exhibit distinct activation mechanisms dictated by the relative strengths of these intramolecular interactions. To elucidate the role of the SH3:linker interaction in the regulation of individual SFKs, we used a synthetic SH3 domain-binding peptide (VSL12) to probe the sensitivity of downregulated c-Src, Hck, Lyn and Fyn to SH3-based activation in a kinetic kinase assay. All four SFKs responded to VSL12 binding with enhanced kinase activity, demonstrating a conserved role for SH3:linker interaction in the control of catalytic function. However, the sensitivity and extent of SH3-based activation varied over a wide range. In addition, autophosphorylation of the activation loops of c-Src and Hck did not override regulatory control by SH3:linker displacement, demonstrating that these modes of activation are independent. Our results show that despite the similarity of their downregulated conformations, individual Src-family members show diverse responses to activation by domain displacement which may reflect their adaptation to specific signaling environments in vivo.

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Section: Introductionmentioning

confidence: 80%

Differential Sensitivity of Src-Family Kinases to Activation by SH3 Domain Displacement

et al. 2014

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“…Sh RNAs targeting c-Yes sequences were also previously described (24). Selection of the c-Yes silenced populations was performed with puromycin (1μg/ml).…”

Section: Methodsmentioning

confidence: 99%

Colon Cancer Cells Escape 5FU Chemotherapy-Induced Cell Death by Entering Stemness and Quiescence Associated with the c-Yes/YAP Axis

Touil

Igoudjil

Corvaisier

et al. 2014

Clinical Cancer Research

278

218

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Purpose Metastasis and drug resistance are the major limitations in the survival and management of cancer patients. This study aimed to identify the mechanisms underlying HT29 colon cancer cell chemoresistance acquired after sequential exposure to 5-fluorouracil (5FU), a classical anticancer drug for treatment of epithelial solid tumors. We examined its clinical relevance in a cohort of colon cancer patients with liver metastases after 5FU-based neoadjuvant chemotherapy and surgery. Results We show that a clonal 5F31 cell population, resistant to 1μM 5FU, express a typical cancer stem cell-like phenotype and enter into a reversible quiescent G0-state upon re-exposure to higher 5FU concentrations. These quiescent cells overexpressed the tyrosine kinase c-Yes that became activated and membrane-associated upon 5FU exposure. This enhanced signaling pathway induced the dissociation of the Yes/YAP (Yes-associated protein) molecular complex and depleted nuclear YAP levels. Consistently, c-Yes silencing decreased nuclear YAP accumulation and induced cellular quiescence in 5F31 cells cultured in 5FU-free medium. Importantly, c-Yes and YAP transcript levels were higher in liver metastases of colon cancer patients after 5FU-based neoadjuvant chemotherapy. Moreover, the c-Yes and YAP levels positively correlated with colon cancer relapse and shorter patient survival (p<0.05 and p<0.025, respectively). Conclusions We identified c-Yes and YAP as potential molecular targets to eradicate quiescent cancer cells and dormant micrometastases during 5FU chemotherapy and resistance and as predictive survival markers for colon cancer.

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“…5 and 6. DISCUSSION c-Yes, similar to other members of the SFKs (e.g., c-Src), is a (proto)oncogene, with its expression intimately related to carcinogenesis (11,29,53,57,58). For instance, overexpression of c-Yes in human colorectal carcinoma cells promotes metastatsis (3), but recent studies have shown that it also plays critical roles in different cellular physiological function, such as growth factor activation, endocytic vesicle-mediated protein trafficking, and cell signaling (11,15,68,69).…”

Section: Knockdown Of C-yes In the Testis In Vivo Disrupts Distributimentioning

confidence: 99%

“…c-Yes (or Yes 1, Yamaguchi sarcoma viral oncogene homolog 1), a nonreceptor protein tyrosine kinase and a member of the Src family kinases (SFKs) and also a proto-oncogene whose expression is upregulated in various cancers, including melanoma (29), colon cancer (58), and brain cancer (53), is also known to be involved in regulating cell cycle and cytokinesis (28). In fact, members of the SFKs are targets of chemotherapy (1,67).…”

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confidence: 99%

c-Yes regulates cell adhesion at the apical ectoplasmic specialization-blood-testis barrier axis via its effects on protein recruitment and distribution

Xiao

Mruk

Cheng

2013

American Journal of Physiology-Endocrinology and Metabolism

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During spermatogenesis, extensive restructuring takes place at the cell-cell interface since developing germ cells migrate progressively from the basal to the adluminal compartment of the seminiferous epithelium. Since germ cells per se are not motile cells, their movement relies almost exclusively on the Sertoli cell. Nonetheless, extensive exchanges in signaling take place between these cells in the seminiferous epithelium. c-Yes, a nonreceptor protein tyrosine kinase belonging to the Src family kinases (SFKs) and a crucial signaling protein, was recently shown to be upregulated at the Sertoli cell-cell interface at the blood-testis barrier (BTB) at stages VIII-IX of the seminiferous epithelial cycle of spermatogenesis. It was also highly expressed at the Sertoli cell-spermatid interface known as apical ectoplasmic specialization (apical ES) at stage V to early stage VIII of the epithelial cycle during spermiogenesis. Herein, it was shown that the knockdown of c-Yes by RNAi in vitro and in vivo affected both Sertoli cell adhesion at the BTB and spermatid adhesion at the apical ES, causing a disruption of the Sertoli cell tight junction-permeability barrier function, germ cell loss from the seminiferous epithelium, and also a loss of spermatid polarity. These effects were shown to be mediated by changes in distribution and/or localization of adhesion proteins at the BTB (e.g., occludin, N-cadherin) and at the apical ES (e.g., nectin-3) and possibly the result of changes in the underlying actin filaments at the BTB and the apical ES. These findings implicate that c-Yes is a likely target of male contraceptive research.testis; c-Yes; nonreceptor protein tyrosine kinase; Sertoli cell; spermatogenesis; seminiferous epithelial cycle; ectoplasmic specialization DURING SPERMATOGENESIS, EXTENSIVE RESTRUCTURING and communication take place at the Sertoli cell-cell and Sertoli-germ cell interface across the seminiferous epithelium to accommodate germ cell movement and to coordinate cellular events that occur simultaneously at different stages of the seminiferous epithelial cycle in the mammalian testis (12,23,48). For instance, at stage VIII of the epithelial cycle, preleptotene spermatocytes, differentiated from type B spermatogonia, residing in the basal compartment traverse the blood-testis barrier (BTB) to enter the adluminal compartment while transforming to leptotene and zygote spermatocytes to prepare for meiosis I/II (23, 48). However, fully developed spermatids that become spermatozoa at the adluminal edge of the tubule lumen undergo spermiation; the release of sperm also takes place at stage VIII of the cycle, involving degeneration of the apical ectoplasmic specialization (apical ES) at the Sertoli-spermatid

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Specific Oncogenic Activity of the Src-Family Tyrosine Kinase c-Yes in Colon Carcinoma Cells

Cited by 37 publications

References 25 publications

Differential Sensitivity of Src-Family Kinases to Activation by SH3 Domain Displacement

Differential Sensitivity of Src-Family Kinases to Activation by SH3 Domain Displacement

Colon Cancer Cells Escape 5FU Chemotherapy-Induced Cell Death by Entering Stemness and Quiescence Associated with the c-Yes/YAP Axis

c-Yes regulates cell adhesion at the apical ectoplasmic specialization-blood-testis barrier axis via its effects on protein recruitment and distribution

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