SRChing for the substrates of Src

Reynolds, Albert B.; Kanner, S B; Bouton, Amy H.; Schaller, Michael D.; Weed, Scott A.; Flynn, Daniel C.; Parsons, J. Thomas

doi:10.1038/onc.2013.416

Cited by 45 publications

(55 citation statements)

References 181 publications

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“…All of these targets are regulated by SRC family kinase activity. 69,70 Western blotting confirmed the observed decrease in total FAK and an increase in ECadherin (data not shown), suggestive of a more epithelial and less invasive state. 71 MCL-1 antagonism also decreased the auto-phosphorylation site Y1148 in EGFR indicating suppression of invasion activity, perhaps due to loss of cSRC activation.…”

Section: Mcl-1 Is a New Regulator Of Protein Kinase Signalling Duringsupporting

confidence: 58%

Myeloid cell leukemia 1 (MCL-1), an unexpected modulator of protein kinase signaling during invasion

Young

Timpson

Gallego‐Ortega

et al. 2017

Cell Adhesion & Migration

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Myeloid cell leukemia-1 (MCL-1), closely related to B-cell lymphoma 2 (BCL-2), has a well-established role in cell survival and has emerged as an important target for cancer therapeutics. We have demonstrated that inhibiting MCL-1 is efficacious in suppressing tumour progression in pre-clinical models of breast cancer and revealed that in addition to its role in cell survival, MCL-1 modulated cellular invasion. Utilizing a MCL-1-specific genetic antagonist, we found two possible mechanisms; firstly MCL-1 directly binds to and alters the phosphorylation of the cytoskeletal remodeling protein, Cofilin, a protein important for cytoskeletal remodeling during invasion, and secondly MCL-1 modulates the levels SRC family kinases (SFKs) and their targets. These data provide evidence that MCL-1 activities are not limited to endpoints of extracellular and intracellular signaling culminating in cell survival as previously thought, but can directly modulate the output of SRC family kinases signaling during cellular invasion. Here we review the pleotropic roles of MCL-1 and discuss the implications of this newly discovered effect on protein kinase signaling for the development of cancer therapeutics.

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Section: Mcl-1 Is a New Regulator Of Protein Kinase Signalling Duringsupporting

confidence: 58%

Myeloid cell leukemia 1 (MCL-1), an unexpected modulator of protein kinase signaling during invasion

Young

Timpson

Gallego‐Ortega

et al. 2017

Cell Adhesion & Migration

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“…To address this further, we assessed both SRC activation and phosphorylation of paxillin. SRC is recruited to phosphorylated Y397 FAK at focal adhesions where it phosphorylates several proteins including paxillin (Y118) [44–46]. FAK also phosphorylates paxillin [47, 48].…”

Section: Resultsmentioning

confidence: 99%

VANGL2 interacts with integrin αv to regulate matrix metalloproteinase activity and cell adhesion to the extracellular matrix

Jessen

2017

Experimental Cell Research

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Planar cell polarity (PCP) proteins are implicated in a variety of morphogenetic processes including embryonic cell migration and potentially cancer progression. During zebrafish gastrulation, the transmembrane protein Vang-like 2 (VANGL2) is required for PCP and directed cell migration. These cell behaviors occur in the context of a fibrillar extracellular matrix (ECM). While it is thought that interactions with the ECM regulate cell migration, it is unclear how PCP proteins such as VANGL2 influence these events. Using an in vitro cell culture model system, we previously showed that human VANGL2 negatively regulates membrane type-1 matrix metalloproteinase (MMP14) and activation of secreted matrix metalloproteinase 2 (MMP2). Here, we investigated the functional relationship between VANGL2, integrin αvβ3, and MMP2 activation. We provide evidence that VANGL2 regulates cell surface integrin αvβ3 expression and adhesion to fibronectin, laminin, and vitronectin. Inhibition of MMP14/MMP2 activity suppressed the cell adhesion defect in VANGL2 knockdown cells. Furthermore, our data show that MMP14 and integrin αv are required for increased proteolysis by VANGL2 knockdown cells. Lastly, we have identified integrin αvβ3 as a novel VANGL2 binding partner. Together, these findings begin to dissect the molecular underpinnings of how VANGL2 regulates MMP activity and cell adhesion to the ECM.

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“…It is well known that CD148 dephosphorylates the suppressive tyrosine residue (Y529) in Src tyrosine kinase and increases its activity [19], [41], [42]. Further, Src is known to play a key role in the establishment of E-cadherin cell-cell adhesion [43], [44]. Therefore, we also evaluated the dephosphorylation of Src Y529.…”

Section: Resultsmentioning

confidence: 99%

CD148 Tyrosine Phosphatase Promotes Cadherin Cell Adhesion

et al. 2014

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CD148 is a transmembrane tyrosine phosphatase that is expressed at cell junctions. Recent studies have shown that CD148 associates with the cadherin/catenin complex and p120 catenin (p120) may serve as a substrate. However, the role of CD148 in cadherin cell-cell adhesion remains unknown. Therefore, here we addressed this issue using a series of stable cells and cell-based assays. Wild-type (WT) and catalytically inactive (CS) CD148 were introduced to A431D (lacking classical cadherins), A431D/E-cadherin WT (expressing wild-type E-cadherin), and A431D/E-cadherin 764AAA (expressing p120-uncoupled E-cadherin mutant) cells. The effects of CD148 in cadherin adhesion were assessed by Ca2+ switch and cell aggregation assays. Phosphorylation of E-cadherin/catenin complex and Rho family GTPase activities were also examined. Although CD148 introduction did not alter the expression levels and complex formation of E-cadherin, p120, and β-catenin, CD148 WT, but not CS, promoted cadherin contacts and strengthened cell-cell adhesion in A431D/E-cadherin WT cells. This effect was accompanied by an increase in Rac1, but not RhoA and Cdc42, activity and largely diminished by Rac1 inhibition. Further, we demonstrate that CD148 reduces the tyrosine phosphorylation of p120 and β-catenin; causes the dephosphorylation of Y529 suppressive tyrosine residue in Src, a well-known CD148 site, increasing Src activity and enhancing the phosphorylation of Y228 (a Src kinase site) in p120, in E-cadherin contacts. Consistent with these findings, CD148 dephosphorylated both p120 and β-catenin in vitro. The shRNA-mediated CD148 knockdown in A431 cells showed opposite effects. CD148 showed no effects in A431D and A431D/E-cadherin 764AAA cells. In aggregate, these findings provide the first evidence that CD148 promotes E-cadherin adhesion by regulating Rac1 activity concomitant with modulation of p120, β-catenin, and Src tyrosine phosphorylation. This effect requires E-cadherin and p120 association.

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SRChing for the substrates of Src

Cited by 45 publications

References 181 publications

Myeloid cell leukemia 1 (MCL-1), an unexpected modulator of protein kinase signaling during invasion

Myeloid cell leukemia 1 (MCL-1), an unexpected modulator of protein kinase signaling during invasion

VANGL2 interacts with integrin αv to regulate matrix metalloproteinase activity and cell adhesion to the extracellular matrix

CD148 Tyrosine Phosphatase Promotes Cadherin Cell Adhesion

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