Src Tyrosine Kinase Is a Novel Direct Effector of G Proteins

Ma, Yongchao; Huang, Jian; Ali, Shariq; Lowry, William E.; Huang, Xin

doi:10.1016/s0092-8674(00)00086-6

Cited by 398 publications

(346 citation statements)

References 74 publications

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“…This stabilized form of Src shows low basal activity, but ECM components such as fibronectin may activate it by inducing conformational changes (Moarefi et al, 1997;Ma et al, 2000). Moreover, it has been described that Src achieves the conformation accessible for the activating phosphorylation by different signaling molecules, such as Cdc2, only after prior phosphorylation at the Csk-specific Tyr527 residue (Stover et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…When phosphorylated at Tyr530, the activity of Src is reduced to low basal levels, thereby protecting cells from the potential oncogenic activity of the src protooncogene (Zheng et al, 2000). The activity of Src phosphorylated at the C-terminal Tyr530 can be increased either by dephosphorylation of Tyr530 or by phosphorylation at other tyrosine residues, for example, after the stimulation of integrin receptors with fibronectin (Moarefi et al, 1997;Ma et al, 2000). It has been shown that Src shows significantly greater protein stability when phosphorylated by Csk (Roskoski, 2004).…”

Section: Re-expression Of Src In Cutl1-knockdown Cells Restores Spreamentioning

confidence: 99%

“…Through phosphorylation at Tyr527, Csk stabilizes Src in a dormant form with low basal activity (Roskoski, 2004). Csk, however, is not able to prevent Src activation through conformational changes on external stimuli such as integrin activation by ECM proteins (Moarefi et al, 1997;Ma et al, 2000). Based on our previous findings which identified the transcription factor CUTL1 as important mediator of cell migration and tumor invasion downstream of TGFb1, we aimed to elucidate the molecular mechanisms and effectors which are crucial for CUTL1-induced tumor cell migration.…”

Section: Introductionmentioning

confidence: 99%

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CUTL1 promotes tumor cell migration by decreasing proteasome-mediated Src degradation

et al. 2007

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Recently, we identified the homeodomain transcription factor CUTL1 as important mediator of cell migration and tumor invasion downstream of transforming growth factor b (TGFb). The molecular mechanisms and effectors mediating the pro-migratory and pro-invasive phenotype induced by CUTL1 have not been elucidated so far. Therefore, the aim of this study was to identify signaling pathways downstream of CUTL1 which are responsible for its effects on tumor cell migration. We found that the reduced motility seen after knock down of CUTL1 by RNA interference is accompanied by a delay in tumor cell spreading. This spreading defect is paralleled by a marked reduction of Src protein levels. We show that CUTL1 leads to Src protein stabilization and activation of Srcregulated downstream signaling molecules such as RhoA, Rac1, Cdc42 and ROCK. In addition, we demonstrate that CUTL1 decreases proteasome-mediated Src protein degradation, possibly via transcriptionally upregulating Cterminal Src kinase (Csk). Based on experiments using Src knockout cells (SYF), we present evidence that Src plays a crucial role in CUTL1-induced tumor cell migration. In conclusion, our findings linking the pro-invasive transcription factor CUTL1 and the Src pathway provide important new insights in the molecular effector pathways mediating CUTL-induced migration and invasion.

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Section: Discussionmentioning

confidence: 99%

Section: Re-expression Of Src In Cutl1-knockdown Cells Restores Spreamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CUTL1 promotes tumor cell migration by decreasing proteasome-mediated Src degradation

et al. 2007

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“…Indeed, we now show that Src plays a critical role in the S1P-stimulated MT1-MMPdependent EGFR transactivation and cell migration. It has been reported that G protein a subunits, such as G ai , directly stimulate Src activity (60), which can lead to MMP-dependent release of EGFR ligands (61). For example, Src activation has been shown to regulate the ADAM-dependent shedding of the L1 adhesion molecule (62).…”

Section: Discussionmentioning

confidence: 99%

Membrane-Type 1 Matrix Metalloproteinase Stimulates Cell Migration through Epidermal Growth Factor Receptor Transactivation

Langlois

Nyalendo

Tomasso

et al. 2007

Molecular Cancer Research

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Proteolysis of extracellular matrix proteins by membrane-type 1 matrix metalloproteinase (MT1-MMP) plays a pivotal role in tumor and endothelial cell migration. In addition to its proteolytic activity, several studies indicate that the proinvasive properties of MT1-MMP also involve its short cytoplasmic domain, but the specific mechanisms mediating this function have yet to be fully elucidated. Having previously shown that the serum factor sphingosine 1-phosphate stimulates MT1-MMP promigratory function through a process that involves its cytoplasmic domain, we now extend these findings to show that this cooperative interaction is permissive to cellular migration through MT1-MMP -dependent transactivation of the epidermal growth factor receptor (EGFR). In the presence of sphingosine 1-phosphate, MT1-MMP stimulates EGFR transactivation through a process that is dependent upon the cytoplasmic domain of the enzyme but not its catalytic activity. The MT1-MMP -induced EGFR transactivation also involves G i protein signaling and Src activities and leads to enhanced cellular migration through downstream extracellular signal-regulated kinase activation. The present study, thus, elucidates a novel role of MT1-MMP in signaling events mediating EGFR transactivation and provides the first evidence of a crucial role of this receptor activity in MT1-MMP promigratory function. Taken together, our results suggest that the inhibition of EGFR may represent a novel target to inhibit MT1-MMP -dependent processes associated with tumor cell invasion and angiogenesis. (Mol Cancer Res 2007;5(6):569 -83)

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“…To determine whether AFAP can directly activate c-Src, an in vitro reconstitution assay was performed (23). Briefly, 20 ng of purified and C-terminal Src kinase-inactivated c-Src (a gift from Dr. X. Huang, Cornell University) in Src kinase buffer (30 mM HEPES, pH 7.4, 5 mM MgCl 2 , 5 mM MnCl 2 , and 10 M ATP) was incubated with 2 g of Src substrate peptide (24) and 10 Ci of [␥-32 P]ATP with purified recombinant cAFAP or AFAP71A (22) in a total 20-l reaction volume at 30°C for 15 min.…”

Section: Methodsmentioning

confidence: 99%

Conversion of Mechanical Force into Biochemical Signaling

Han

Bai

Lodyga

et al. 2004

Journal of Biological Chemistry

144

132

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Physical forces play important roles in regulating cell proliferation, differentiation, and death by activating intracellular signal transduction pathways. How cells sense mechanical stimulation, however, is largely unknown. Most studies focus on cellular membrane proteins such as ion channels, integrins, and receptors for growth factors as mechanosensory units. Here we show that mechanical stretch-induced c-Src protein tyrosine kinase activation is mediated through the actin filament-associated protein (AFAP). Distributed along the actin filaments, AFAP can directly active c-Src through binding to its Src homology 3 and/or 2 domains. Mutations at these specific binding sites on AFAP blocked mechanical stretch-induced c-Src activation. Therefore, mechanical force can be transmitted along the cytoskeleton, and interaction between cytoskeletal associated proteins and enzymes related to signal transduction may convert physical forces into biochemical reactions. Cytoskeleton deformation-induced proteinprotein interaction via specific binding sites may represent a novel intracellular mechanism for cells to sense mechanical stimulation.

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Src Tyrosine Kinase Is a Novel Direct Effector of G Proteins

Cited by 398 publications

References 74 publications

CUTL1 promotes tumor cell migration by decreasing proteasome-mediated Src degradation

CUTL1 promotes tumor cell migration by decreasing proteasome-mediated Src degradation

Membrane-Type 1 Matrix Metalloproteinase Stimulates Cell Migration through Epidermal Growth Factor Receptor Transactivation

Conversion of Mechanical Force into Biochemical Signaling

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