Protein Tyrosine Phosphatase-PEST and β8 Integrin Regulate Spatiotemporal Patterns of RhoGDI1 Activation in Migrating Cells

Abstract

f Directional cell motility is essential for normal development and physiology, although how motile cells spatiotemporally activate signaling events remains largely unknown. Here, we have characterized an adhesion and signaling unit comprised of protein tyrosine phosphatase (PTP)-PEST and the extracellular matrix (ECM) adhesion receptor ␤8 integrin that plays essential roles in directional cell motility. ␤8 integrin and PTP-PEST form protein complexes at the leading edge of migrating cells and balance patterns of Rac1 and Cdc42 signaling by controlling the subcellular localization and phosphorylation status of Rho GDP dissociation inhibitor 1 (RhoGDI1). Translocation of Src-phosphorylated RhoGDI1 to the cell's leading edge promotes local activation of Rac1 and Cdc42, whereas dephosphorylation of RhoGDI1 by integrin-bound PTP-PEST promotes RhoGDI1 release from the membrane and sequestration of inactive Rac1/Cdc42 in the cytoplasm. Collectively, these data reveal a finely tuned regulatory mechanism for controlling signaling events at the leading edge of directionally migrating cells.

Glioblastoma stem cells exploit the αvβ8 integrin-TGFβ1 signaling axis to drive tumor initiation and progression

“…59–62 We have reported previously that αvβ8 integrin-mediated signaling via Rho GTPases regulatory factors is essential for tumor cell invasion in the brain. 42,63,64 It will be interesting to determine whether αvβ8 integrin or its intracellular signaling effectors are differentially regulated in GSCs following surgery and anti-vascular therapies, thus contributing to tumor recurrence and/or invasion. These studies may extend beyond GBM; for example, ITGB8 expression is upregulated in peripheral nerve sheath tumors, 65 and in brain metastases, 66 suggesting that targeting this integrin may impact tumor growth in other cancer types.…”

Downregulation of ARHGDIA contributes to human glioma progression through activation of Rho GTPase signaling pathway

“…When silencing ARHGDIA gene expression leads to elevated levels of GTP-bound Rho proteins, which results in diminishing cell polarity and invasion [19]. Moreover, phosphorylation of ARHGDIA on Y156 leads to deposition of Rac1/Cdc42 proteins and enabling their activation to promote directional cell motility [20]. These indicate that the ARHGDIA protein affects the activation of Rho proteins mainly via coupling other proteins such as αvβ8 integrin.…”

PTP-PEST controls EphA3 activation and ephrin-induced cytoskeletal remodelling

“…It interacts with prominent focal adhesion components, such as p130Cas (also known as BCAR1) (Garton et al, 1996) and paxillin (Shen et al, 1998), and controls cell shape and adhesion by modulating focal adhesion assembly and turnover. PTP-PEST also coordinates directed cell movement by differentially regulating Rac1 and RhoA activities through dephosphorylation of Vav2 and p190RhoGAP (also known as ARHGAP35), respectively (Angers-Loustau et al, 1999;Sastry et al, 2002Sastry et al, , 2006, and by controlling the subcellular localization and phosphorylation status of Rho GDP dissociation inhibitor 1 (RhoGDI1, also known as ARHGDIA) (Lee et al, 2015b). Intriguingly, both overexpression (Garton and Tonks, 1999) and gene deletion (Angers-Loustau et al, 1999;Sastry et al, 2006) result in impaired cell motility and spreading, indicating that balanced expression levels of PTP-PEST are required for the accurate control of cell morphology and adhesion that is essential for development (Mathew et al, 2008;Taieb et al, 2008).…”