Tyrosine phosphorylation of C-Cbl facilitates adhesion and spreading while suppressing anchorage-independent growth of V-Abl-transformed NIH3T3 fibroblasts

Feshchenko, Elena A; Shore, Scott K.; Tsygankov, Alexander Y.

doi:10.1038/sj.onc.1202672

Cited by 50 publications

(100 citation statements)

References 78 publications

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“…Indeed, our results indicated that interaction between SLAP and c-Cbl enhances spreading of v-Abl-3T3 cells on FN-coated surfaces (Figure 5c and d). Consistent with the role that cell spreading plays in adhesion of v-Abl-3T3 fibroblasts (Feshchenko et al, 1999;Teckchandani et al, 2001), expression of ectopic SLAP increased adhesion of v-Abl-3T3 cells expressing ectopic c-Cbl in the absence of FN pre-coating (Figure 7d and data not shown). In agreement with these findings, siRNA-mediated depletion of endogenous SLAP in v-Abl-3T3 cells expressing ectopic SLAP enhances c-Cbl-mediated cell spreading and adhesion G Swaminathan et al c-Cbl resulted in a significant decrease in cell spreading ( Figure 6).…”

Section: Discussionsupporting

confidence: 79%

“…This fraction is more tyrosinephosphorylated and binds p85-PI3K with a higher stoichiometry compared with cytosolic c-Cbl (Figure 1). Tyrosine phosphorylation of c-Cbl and interaction of c-Cbl with PI3K are indispensable for c-Cbl-dependent signaling that leads to cytoskeletal effects in v-Abl-3T3 fibroblasts (Feshchenko et al, 1999;Teckchandani et al, 2001Teckchandani et al, , 2005b. Furthermore, functions of PI3K and several proteins that may act downstream of c-Cbl in this system have been shown to require their membrane localization (Abassi and Vuori, 2002;Innocenti et al, 2003;Arthur et al, 2004).…”

Section: Discussionmentioning

confidence: 97%

“…Our current results demonstrate that tyrosine phosphorylation of membrane-associated c-Cbl is especially high (Figure 1), in agreement with the membrane localization of v-Abl. Tyrosine-phosphorylated c-Cbl recruits p85-PI3K and other signaling proteins, thus triggering downstream signal transduction resulting inactivation of small GTPases, including Rac1 (Feshchenko et al, 1999;Teckchandani et al, 2001). It appears that an increase in association of c-Cbl with p85-PI3K is an essential part of the effect of SLAP on c-Cbldependent cytoskeletal events.…”

Section: Discussionmentioning

confidence: 99%

“…This effect was dependent on tyrosine phosphorylation of c-Cbl and resultant recruitment of p85-phosphatidylinositol-3-kinase (PI3K) leading to activation of Rho-family GTPases, primarily Rac1. Furthermore, c-Cbl was found to promote migration of v-Abl-3T3 fibroblasts, which also requires interaction of c-Cbl with PI3K and activation of Rac1 (Feshchenko et al, 1999;Teckchandani et al, 2001Teckchandani et al, , 2005b.…”

mentioning

confidence: 97%

“…c-Cbl is both an E3 ubiquitin ligase involved in the negative regulation of protein tyrosine kinases (PTK) (Levkowitz et al, , 2000Miyake et al, 1999;Waterman et al, 1999;Rao et al, 2001;Yokouchi et al, 2001) and an adaptor protein involved in multiple biological phenomena, including cytoskeletal events (Tanaka et al, 1996;Ojaniemi et al, 1997;Meng and Lowell, 1998;Sanjay et al, 2001;Scaife et al, 2003a, b;Haglund et al, 2004). In several instances, tyrosine phosphorylation of c-Cbl has been shown to be crucial for c-Cbl-mediated adaptor effects (Ojaniemi et al, 1997;Feshchenko et al, 1999;Sanjay et al, 2001). …”

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confidence: 99%

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c-Cbl-facilitated cytoskeletal effects in v-Abl-transformed fibroblasts are regulated by membrane association of c-Cbl

2007

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The multi-functional protein c-Cbl is an important modulator of actin cytoskeletal dynamics in diverse biological systems. We had previously reported that c-Cbl facilitates cell spreading and adhesion and suppresses anchorage-independent growth of v-Abl-transformed fibroblasts. To assess the importance of membrane localization of c-Cbl for the observed effects of c-Cbl in v-Abl-3T3 cells, we first mapped the membrane interactive domain(s) of c-Cbl. Our studies indicate that localization of c-Cbl to the membrane is likely to be mediated by the tyrosine kinase binding (TKB) domain and the proline-rich region of c-Cbl, whereas C-terminal tyrosine phosphorylation does not play a role. The association of v-Cbl, which encompasses the TKB domain, with the membrane was unusual as it was not entirely dependent on SH2-phosphotyrosine interactions. Our studies further demonstrate that Src-like adaptor protein (SLAP), which binds to v-Cbl in a tyrosine phosphorylation-independent manner, facilitates membrane association of Cbl. The interaction between c-Cbl and SLAP in v-Abl-3T3 cells positively influenced c-Cbl-mediated spreading and adhesion of these cells. SLAP appears to exert its effects not simply by increasing the amount of c-Cbl in the membrane but by facilitating binding of p85-phosphatidylinositol-3-kinase (PI3K) with membrane-associated c-Cbl.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 97%

mentioning

confidence: 99%

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c-Cbl-facilitated cytoskeletal effects in v-Abl-transformed fibroblasts are regulated by membrane association of c-Cbl

2007

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An essential role of ubiquitination in Cbl-mediated negative regulation of the Src-family kinase Fyn

Rao

Ghosh

Zhou

et al. 2002

Signal Transduction

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The Cbl family of ubiquitin ligases function as negative regulators of activated receptor tyrosine kinases by facilitating their ubiquitination and subsequent lysosomal targeting. Here, we have investigated the role of Cbl ubiquitin ligase activity in the negative regulation of a non-receptor tyrosine kinase, the Src-family kinase Fyn. Using primary embryonic fibroblasts from Cbl +/+ and Cbl −/− mice, we demonstrate that endogenous Cbl mediates the ubiquitination of Fyn and dictates the rate of Fyn turnover. By analyzing CHO-TS20 cells with a temperature-sensitive ubiquitin activating enzyme, we demonstrate that intact cellular ubiquitin machinery is required for Cblinduced degradation of Fyn. Analyses of Cbl mutants, with mutations in or near the RING finger domain, in 293T cells revealed that the ubiquitin ligase activity of Cbl is essential for Cbl-induced degradation of Fyn by the proteasome pathway. Finally, use of a SRE-luciferase reporter demonstrated that Cbl-dependent negative regulation of Fyn function requires the region of Cbl that mediates the ubiquitin ligase activity. Given the conservation of structure between various Src-family kinases and the ability of Cbl to interact with multiple members of this family, Cbl-dependent ubiquitination could serve a general role to negatively regulate activated Src-family kinases.

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c‐Cbl regulates glioma invasion through matrix metalloproteinase 2

Lee¹,

Tsygankov²

2010

J of Cellular Biochemistry

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c-Cbl, a multifunctional adaptor and an E3 ubiquitin ligase, plays a role in such cytoskeleton-mediated events as cell adhesion and migration. Invasiveness of human glioma is dependent on cell adhesion, migration, and degradation of extracellular matrix (ECM). However, the function of c-Cbl in glioma invasion has never been investigated. We report here, for the first time, that c-Cbl plays a positive role in the invasion of ECM by SNB19 glioma cells. RNAi-mediated depletion of c-Cbl decreases SNB19 cell invasion and expression of matrix metalloproteinase 2 (MMP2). Consistent with these findings, SNB19 cells expressing wild-type, but not mutant c-Cbl show increased invasion and MMP2 expression. We demonstrate that the observed role of c-Cbl in invasion of SNB19 cells is not mediated by the previously shown effects of c-Cbl on cell adhesion and migration or on EGFR signaling. Together, our results suggest that c-Cbl promotes glioma invasion through up-regulation of MMP2.

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Tyrosine phosphorylation of C-Cbl facilitates adhesion and spreading while suppressing anchorage-independent growth of V-Abl-transformed NIH3T3 fibroblasts

Cited by 50 publications

References 78 publications

c-Cbl-facilitated cytoskeletal effects in v-Abl-transformed fibroblasts are regulated by membrane association of c-Cbl

c-Cbl-facilitated cytoskeletal effects in v-Abl-transformed fibroblasts are regulated by membrane association of c-Cbl

An essential role of ubiquitination in Cbl-mediated negative regulation of the Src-family kinase Fyn

c‐Cbl regulates glioma invasion through matrix metalloproteinase 2

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