PTP1B triggers integrin-mediated repression of myosin activity and modulates cell contractility

Abstract

Cell contractility and migration by integrins depends on precise regulation of protein tyrosine kinase and Rho-family GTPase activities in specific spatiotemporal patterns. Here we show that protein tyrosine phosphatase PTP1B cooperates with β3 integrin to activate the Src/FAK signalling pathway which represses RhoA-myosin-dependent contractility. Using PTP1B null (KO) cells and PTP1B reconstituted (WT) cells, we determined that some early steps following cell adhesion to fibronectin and vitronectin occurred robustly in WT cells, including aggregation of β3 integrins and adaptor proteins, and activation of Src/FAK-dependent signalling at small puncta in a lamellipodium. However, these events were significantly impaired in KO cells. We established that cytoskeletal strain and cell contractility was highly enhanced at the periphery of KO cells compared to WT cells. Inhibition of the Src/FAK signalling pathway or expression of constitutive active RhoA in WT cells induced a KO cell phenotype. Conversely, expression of constitutive active Src or myosin inhibition in KO cells restored the WT phenotype. We propose that this novel function of PTP1B stimulates permissive conditions for adhesion and lamellipodium assembly at the protruding edge during cell spreading and migration.

ZINC40099027 activates human focal adhesion kinase by accelerating the enzymatic activity of the FAK kinase domain

“…It, therefore, seemed an attractive hypothesis that Zn27 might interact with one of the classical tyrosine‐specific nonreceptor protein phosphatases (SHP2, PTP1B, PTP‐PEST) that have been identified as key players in modulating both FAK activity 45–47 and cell migration 48 . Although PTP‐PEST modulates FAK‐Tyr‐397 dephosphorylation, 44 FAK activity, 46,49 and cell migration, 50,51 PTP‐PEST inhibition, accentuated basal FAK phosphorylation, but did not prevent Zn27 further stimulation of FAK Tyr‐397. Similarly, although the tyrosine phosphatase PTP1B also dephosphorylates FAK, 52 we did not observe any change in PTP1B/FAK activity with Zn27.…”

“…as key players in modulating both FAK activity [45][46][47] and cell migration. 48 Although PTP-PEST modulates FAK-Tyr-397 dephosphorylation, 44 FAK activity, 46,49 and cell migration, 50,51 PTP-PEST inhibition, accentuated basal FAK phosphorylation, but did not prevent Zn27 further stimulation of FAK Tyr-397. Similarly, although the tyrosine phosphatase PTP1B also dephosphorylates FAK, 52 we did not observe any change in PTP1B/FAK activity with Zn27.…”

Inhibition of protein‐tyrosine phosphatase 1B phosphorylation enhances early adhesion of mesenchymal stem cells to facilitate fabrication of tissue‐engineered bone

“…Protein‐tyrosine phosphatase 1B (PTP1B) is a major activator of Src (Bjorge, Pang, & Fujita, ; Monteleone et al, ) and localizes to early cell–matrix adhesion sites (Hernandez, Sala, Balsamo, Lilien, & Arregui, ) as a promotor of integrin adhesion (Arregui, Balsamo, & Lilien, ; Cheng, Bal, Kennedy, & Tremblay, ; Gonzalez Wusener, Gonzalez, Nakamura, & Arregui, ; Hernandez et al, ). However, cadherin adhesion complexes, which mainly conduct homotypic cell–cell adhesion, competitively occupy PTP1B when it is phosphorylated at Y152 (Hernandez, Wehrendt, & Arregui, ; Lilien & Balsamo, ; Xu et al, ; Xu, Arregui, Lilien, & Balsamo, ).…”