Cell signaling does not occur randomly over the cell surface, but is integrated within cholesterol-enriched membrane domains, termed rafts. By targeting SHP-2 to raft domains or to a non-raft plasma membrane fraction, we studied the functional role of rafts in signaling. Serum-depleted, nonattached cells expressing the raft SHP-2 form, but not non-raft SHP-2, display signaling events resembling those observed after fibronectin attachment, such as β1 integrin clustering, 397Y-FAK phosphorylation, and ERK activation, and also increases Rho-GTP levels. Expression of the dominant negative N19Rho abrogates raft-SHP-2–induced signaling, suggesting that Rho activation is a downstream event in SHP-2 signaling. Expression of a catalytic inactive SHP-2 mutant abrogates the adhesion-induced feedback inhibition of Rho activity, suggesting that SHP-2 contributes to adhesion-induced suppression of Rho activity. Because raft recruitment of SHP-2 occurs physiologically after cell attachment, these results provide a mechanism by which SHP-2 may influence cell adhesion and migration by spatially regulating Rho activity.
Specific SHP-2 partitioning in raft domains triggers integrin-mediated signaling via Rho activation
The online version of this article contains supplemental material.
Abbreviations used in this paper: CD, methyl-β-cyclodextrin; Cho, cholesterol; CTx, cholera toxin β-subunit; DRM, detergent-resistant membrane; ECM, extracellular matrix; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; Fn, fibronectin; FRNK, FAK-related nonkinase; GEF, guanine-nucleotide exchange factors; GAP, GTPase-activating proteins; MAPK, mitogen-activated protein kinase; pNPP, p-nitrophenyl phosphate; PTP, protein tyrosine phosphatase; SFK, Src-family kinase; TfR transferrin receptor.
Rosa Ana Lacalle, Emilia Mira, Concepción Gómez-Moutón, Sonia Jiménez-Baranda, Carlos Martínez-A., Santos Mañes; Specific SHP-2 partitioning in raft domains triggers integrin-mediated signaling via Rho activation . J Cell Biol 15 April 2002; 157 (2): 277–289. doi: https://doi.org/10.1083/jcb.200109031
Download citation file:
Sign in
Client Account
Sign in via your Institution
Sign in via your InstitutionEmail alerts
Advertisement
Advertisement