SH2 Domain Binding: Diverse FLVRs of Partnership

Chehayeb, Rachel Jaber; Boggon, Titus J.

doi:10.3389/fendo.2020.575220

Cited by 25 publications

(26 citation statements)

References 76 publications

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“…In contrast, the SH2 domains are modular phosphotyrosine-binding domains that consists of an approximately 100 amino acid residues, which fold into structure with two α-helices (a1 and a2) that packed against each side of a central three-stranded β-sheet [ 37 ]. The SH2 domain structure has a conserved argine-containing recognition pocket for binding phosphotyrosine residues and another pocket for binding hydrophobic residues C-terminal to the phosphotyrosine motif.…”

Section: Introductionmentioning

confidence: 99%

Src family kinases, adaptor proteins and the actin cytoskeleton in epithelial-to-mesenchymal transition

Ortiz

Mikhailova

et al. 2021

Cell Commun Signal

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Over a century of scientific inquiry since the discovery of v-SRC but still no final judgement on SRC function. However, a significant body of work has defined Src family kinases as key players in tumor progression, invasion and metastasis in human cancer. With the ever-growing evidence supporting the role of epithelial-mesenchymal transition (EMT) in invasion and metastasis, so does our understanding of the role SFKs play in mediating these processes. Here we describe some key mechanisms through which Src family kinases play critical role in epithelial homeostasis and how their function is essential for the propagation of invasive signals.

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Section: Introductionmentioning

confidence: 99%

Src family kinases, adaptor proteins and the actin cytoskeleton in epithelial-to-mesenchymal transition

Ortiz

Mikhailova

et al. 2021

Cell Commun Signal

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“…We extended this approach to test the importance of the BCAR3 SH2 domain and Cas binding site for degradation. To inactivate the BCAR3 SH2 domain, we created an arginine to lysine at residue 177 (R177K), which lies in the consensus FLVRES motif and is required to bind the pY phosphate ( Jaber Chehayeb and Boggon, 2020 ; Marengere and Pawson, 1994 ). Cul5-depletion increased the level of BCAR3 R177K ( Figure 5d ), suggesting this mutant is still phosphorylated at Y117 and targeted by CRL5.…”

Section: Resultsmentioning

confidence: 99%

A Cas-BCAR3 co-regulatory circuit controls lamellipodia dynamics

Steenkiste

Berndt

Pilling

et al. 2021

eLife

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Integrin adhesion complexes regulate cytoskeletal dynamics during cell migration. Adhesion activates phosphorylation of integrin-associated signaling proteins, including Cas (p130Cas, BCAR1), by Src-family kinases. Cas regulates leading-edge protrusion and migration in cooperation with its binding partner, BCAR3. However, it has been unclear how Cas and BCAR3 cooperate. Here, using normal epithelial cells, we find that BCAR3 localization to integrin adhesions requires Cas. In return, Cas phosphorylation, as well as lamellipodia dynamics and cell migration, requires BCAR3. These functions require the BCAR3 SH2 domain and a specific phosphorylation site, Tyr 117, that is also required for BCAR3 downregulation by the ubiquitin-proteasome system. These findings place BCAR3 in a co-regulatory positive-feedback circuit with Cas, with BCAR3 requiring Cas for localization and Cas requiring BCAR3 for activation and downstream signaling. The use of a single phosphorylation site in BCAR3 for activation and degradation ensures reliable negative feedback by the ubiquitin-proteasome system.

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“…To inhibit Cas binding, we used the aforementioned L744E/R748E mutant (BCAR3 EE ). To inactivate the BCAR3 SH2 domain, we created an arginine to lysine at residue 177 (R177K), which lies in the consensus FLVRES motif and is required to bind the pY phosphate (Jaber Chehayeb et al, 2020, Marengere et al, 1994). This mutation did not inhibit Cas binding (Figure 5b.…”

Section: Resultsmentioning

confidence: 99%

A Cas-BCAR3 co-regulatory circuit controls lamellipodia dynamics

Steenkiste

Berndt

Pilling

et al. 2021

Preprint

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Cell migration involves positive and negative feedback loops that coordinate integrin engagement with lamellipodial protrusion. A key player is Cas (p130Cas, BCAR1), whose integrin-induced phosphorylation stimulates actin polymerization at the cell edge and formation of a ruffling lamellipodium. Cas phosphorylation also stimulates Cas downregulation by the ubiquitin-proteasome pathway, ensuring negative feedback. Although Cas appears to be mechanosensitive, it remains unclear how integrins stimulate Cas phosphorylation. Cas associates with integrin adhesions through its N and C termini. The C terminus of Cas binds to an SH2 domain protein, BCAR3, but the importance of this interaction is unclear. Here, we find that, like Cas, BCAR3 is also activated by phosphorylation and inactivated by the ubiquitin-proteasome system. BCAR3 is necessary for Cas phosphorylation but not Cas localization. Instead, BCAR3 requires Cas for localization. We identify a single phosphorylation site in BCAR3 that is required for both Cas activation and for BCAR3 turnover. Mutation of this site inhibits BCAR3 turnover, Cas phosphorylation, lamellipodium ruffling and migration. This places BCAR3 in a co-regulatory positive-feedback circuit with Cas, with BCAR3 requiring Cas for localization and Cas requiring BCAR3 for activation. The use of a single phosphorylation site in BCAR3 for activation and degradation ensures reliable negative feedback by the ubiquitin-proteasome system.

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SH2 Domain Binding: Diverse FLVRs of Partnership

Cited by 25 publications

References 76 publications

Src family kinases, adaptor proteins and the actin cytoskeleton in epithelial-to-mesenchymal transition

Src family kinases, adaptor proteins and the actin cytoskeleton in epithelial-to-mesenchymal transition

A Cas-BCAR3 co-regulatory circuit controls lamellipodia dynamics

A Cas-BCAR3 co-regulatory circuit controls lamellipodia dynamics

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