Shc and Fak Differentially Regulate Cell Motility and Directionality Modulated by Pten

Abstract

Cell migration is modulated by regulatory molecules such as growth factors, oncogenes, and the tumor suppressor PTEN. We previously described inhibition of cell migration by PTEN and restoration of motility by focal adhesion kinase (FAK) and p130 Crk-associated substrate (p130Cas). We now report a novel pathway regulating random cell motility involving Shc and mitogen-activated protein (MAP) kinase, which is downmodulated by PTEN and additive to a FAK pathway regulating directional migration. Overexpression of Shc or constitutively activated MEK1 in PTEN- reconstituted U87-MG cells stimulated integrin- mediated MAP kinase activation and cell migration. Conversely, overexpression of dominant negative Shc inhibited cell migration; Akt appeared uninvolved. PTEN directly dephosphorylated Shc. The migration induced by FAK or p130Cas was directionally persistent and involved extensive organization of actin microfilaments and focal adhesions. In contrast, Shc or MEK1 induced a random type of motility associated with less actin cytoskeletal and focal adhesion organization. These results identify two distinct, additive pathways regulating cell migration that are downregulated by tumor suppressor PTEN: one involves Shc, a MAP kinase pathway, and random migration, whereas the other involves FAK, p130Cas, more extensive actin cytoskeletal organization, focal contacts, and directionally persistent cell motility. Integration of these pathways provides an intracellular mechanism for regulating the speed and the directionality of cell migration.

The c-Abl tyrosine kinase contributes to the transient activation of MAP kinase in cells plated on fibronectin

“…One substrate for Erks that can lead to motility and changes in actin organization is myosin light chain kinase (Klemke et al, 1997). Additionally, recent work showed that both FAK and Shc could work through Erks to promote integrin-mediated cell migration and cytoskeletal organization (Gu et al, 1999). A role for MAP kinase and c-Abl in integrin signaling is therefore consistent with the altered cell migration and cytoskeletal organization observed in cAbl-de®cient mice (Koleske et al, 1998).…”

“…However, the activation of Erks when cells are replated on FN is highly transient and is therefore unlikely to promote progression through G1. Integrin activation of MAP kinase has also been implicated in cytoskeletal organization and cell migration (Anand-Apte et al, 1997; Klemke et al, 1997;Gu et al, 1999). One substrate for Erks that can lead to motility and changes in actin organization is myosin light chain kinase (Klemke et al, 1997).…”

Carbon monoxide donors or heme oxygenase-1 (HO-1) overexpression blocks interleukin-18-mediated NF-κB–PTEN-dependent human cardiac endothelial cell death

“…Activation of NF-κB leads to suppression or activation of PTEN expression depending on the stimulus and the cell type [31,32]. We previously demonstrated that IL-18 stimulates PTEN induction in EC via NF-κB-activation [12].…”

Neuregulin activates erbB2-dependent src/FAK signaling and cytoskeletal remodeling in isolated adult rat cardiac myocytes

“…Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase critical for the formation of focal adhesion complexes (FAC) and cell spreading, motility and survival [12]. FAK is a substrate of Src, and both FAK and Src are activated in cancer cells overexpressing erbB2 or stimulated with erbB ligand [13,14].…”