c-Cbl facilitates fibronectin matrix production by v-Abl-transformed NIH3T3 cells via activation of small GTPases

Teckchandani, Anjali; Feshchenko, Elena A; Tsygankov, Alexander Y.

doi:10.1038/sj.onc.1204246

Cited by 17 publications

(37 citation statements)

References 81 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: 78%

“…c-Cbl-mediated spreading of v-Abl-3T3 fibroblasts increases FN deposition, which in turn enhances adhesion of these cells in culture (Teckchandani et al, 2001). Consistent with these results, cells coexpressing c-Cbl and SLAP displayed increased adhesion in the absence of FN pre-coating over v-Abl-3T3 cells with c-Cbl alone, whereas demonstrating no discernable difference on FN-coated surfaces (data not shown).…”

Section: Slap Enhances C-cbl-mediated Cytoskeletal Effectssupporting

confidence: 74%

“…SLAP enhances c-Cbl-mediated cell spreading and adhesion G Swaminathan et al firmly established (Teckchandani et al, 2001(Teckchandani et al, , 2005b and because the p85-PI3K:c-Cbl ratio is higher for membrane-associated c-Cbl than for cytosolic c-Cbl (Figure 1c). We immunoprecipitated c-Cbl from v-Abl-3T3 cells expressing ectopic c-Cbl with or without ectopic SLAP and immunoblotted the obtained immune complexes for p85.…”

Section: Of Two-independent Experiments) Is Presented In (G)mentioning

confidence: 75%

“…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: 95%

“…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.…”

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confidence: 97%

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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: 78%

Section: Slap Enhances C-cbl-mediated Cytoskeletal Effectssupporting

confidence: 74%

Section: Of Two-independent Experiments) Is Presented In (G)mentioning

confidence: 75%

Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 97%

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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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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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The Cbl family proteins: Ring leaders in regulation of cell signaling

Swaminathan

Tsygankov

2006

Journal Cellular Physiology

281

349

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The proto-oncogenic protein c-Cbl was discovered as the cellular form of v-Cbl, a retroviral transforming protein. This was followed over the years by important discoveries, which identified c-Cbl and other Cbl-family proteins as key players in several signaling pathways. c-Cbl has donned the role of a multivalent adaptor protein, capable of interacting with a plethora of proteins, and has been shown to positively influence certain biological processes. The identity of c-Cbl as an E3 ubiquitin ligase unveiled the existence of an important negative regulatory pathway involved in maintaining homeostasis in protein tyrosine kinase (PTK) signaling. Recent years have also seen the emergence of novel regulators of Cbl, which have provided further insights into the complexity of Cbl-influenced pathways. This review will endeavor to provide a summary of current studies focused on the effects of Cbl proteins on various biological processes and the mechanism of these effects. The major sections of the review are as follows: Structure and genomic organization of Cbl proteins; Phosphorylation of Cbl; Interactions of Cbl; Localization of Cbl; Mechanism of effects of Cbl: (a) Ubiquitylation-dependent events: This section elucidates the mechanism of Cbl-mediated downregulation of EGFR and details the PTK and non-PTKs targeted by Cbl. In addition, it addresses the functional requirements for E3 Ubiquitin ligase activity of Cbl and negative regulation of Cbl-mediated downregulation of PTKs, (b) Adaptor functions: This section discusses the mechanisms of adaptor functions of Cbl in mitogen-activated protein kinase (MAPK) activation, insulin signaling, regulation of Ras-related protein 1 (Rap1), PI-3 0 kinase signaling, and regulation of Rho-family GTPases and cytoskeleton; Biological functions: This section gives an account of the diverse biological functions of Cbl and includes the role of Cbl in transformation, T-cell signaling and thymus development, B-cell signaling, mast-cell degranulation, macrophage functions, bone development, neurite growth, platelet activation, muscle degeneration, and bacterial invasion; Conclusions and perspectives.

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c-Cbl facilitates fibronectin matrix production by v-Abl-transformed NIH3T3 cells via activation of small GTPases

Cited by 17 publications

References 81 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

c‐Cbl regulates glioma invasion through matrix metalloproteinase 2

The Cbl family proteins: Ring leaders in regulation of cell signaling

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