Src Homology Domain 2-containing Tyrosine Phosphatase 2 Associates with Intercellular Adhesion Molecule 1 to Regulate Cell Survival

Abstract

Intracellular adhesion molecule-1 (ICAM-1, also termed CD54)1 is a receptor expressed on diverse cell types and belongs to the Ig-like family of proteins. Endothelial cells (ECs) express very low amounts of ICAM-1 and require stimulation with cytokines tumor necrosis factor-␣ (TNF␣) or interleukin-1 to upregulate ICAM-1 levels (1-3). ICAM-1 functions as a costimulatory molecule on antigen-presenting cells to activate major histocompatability complex class II restricted T-cells and on other cell types in association with major histocompatability complex class I to activate cytotoxic T-cells. The recognition of ICAM-1 by ␤ 2 -integrins results in the adhesion of leukocytes to the endothelium and in the extravasation of leukocytes to sites of inflammation (3-5). The extravasation of leukocytes also occurs through a process involving ICAM-1 and the plasma protein fibrinogen (Fg). In this process, the integrin-bound Fg interacts with ICAM-1, mediating the bridging between blood cells and ECs (6 -9). TNF␣-stimulated ECs interact with Fg primarily through ICAM-1 (2, 10). A region within the first Ig-like motif of ICAM-1, ICAM-1-(8 -21), and a segment within the ␥-chain of Fg, Fg ␥-(117-133), participate in Fg-ICAM-1-mediated cellular bridging, cell survival, and proliferation (10 -15).The 28-amino acid cytoplasmic tail of ICAM-1 lacks the consensus sequence required for intrinsic kinase activity. Moreover, ICAM-1 lacks the motifs resembling the Src homology domains (SH) that can recruit phosphorylated proteins at the cytoplasmic, membrane-proximal site (16). Nevertheless, Fg-ICAM-1 ligation in Raji B-cells results in proliferative signals that causes 2-3-fold increase in the phosphorylation of pp60Src and of the extracellular signal-regulated kinase (ERK) (13,14). However, the ligation of TNF␣-stimulated ECs to Fg results in a dramatic increase (8 -10-fold) in ERK phosphorylation, which is implicated in EC survival and in preventing TNF␣-mediated apoptosis (15). In other studies, the ligation of ICAM-1 from EC derived from rat brain microvessels with ␤ 2 -integrins from activated T-cells resulted in the phosphorylation of a Src kinase substrate, cortactin (17). The activation of the small molecular weight GTPase Rho, following cross-linking of ECs with ICAM-1 antibodies, has been implicated in leukocyte transmigration (18,19). ICAM-1 cross-linking in Blymphoma and in T-cells activated the Src family kinase Lyn and inactivated Cdc2 kinase, respectively (20,21).The cytoplasmic sequence of several Ig-like receptors such as CD22 (22-24), CD33 (25), platelet endothelial cell adhesion molecule-1 (PECAM-1) (26,27), Fc␥RIIB (28,29), and the killer cell inhibitory receptor (30, 31) contain module(s) termed immune receptor tyrosine-binding inhibition motifs (ITIM). The ITIM consensus sequence (I/V/L)XYXX(L/V), when phosphorylated, associates with the Src homology 2 (SH2) domain-containing phosphatases SHP-1, SHP-2, and SHIP-1 (SH2-containing inositol polyphosphate 5-phosphatase). These cytosolic phosphatases down-regulate tyrosi...

Cross-Talk between ICAM-1 and GM-CSF Receptor Signaling Modulates Eosinophil Survival and Activation

“…Furthermore, coprecipitation and affinity pull-down experiments suggested an important role for the Shp2 adaptor molecule in mediating this interaction. This is in agreement with a previous report for the role of Shp2 in mediating prosurvival signaling from ICAM-1 in endothelial cells stimulated with TNF-␣ (32). In this study, the ICAM-1-Shp2 interaction was proposed as a limiting factor for the TNF-␣ antiapoptotic effect (32), analogous to the cross-talk between GMR␤ and ICAM-1 demonstrated here.…”

“…This is in agreement with a previous report for the role of Shp2 in mediating prosurvival signaling from ICAM-1 in endothelial cells stimulated with TNF-␣ (32). In this study, the ICAM-1-Shp2 interaction was proposed as a limiting factor for the TNF-␣ antiapoptotic effect (32), analogous to the cross-talk between GMR␤ and ICAM-1 demonstrated here. Tyrosine-phosphorylated Shp2 functions as an adapter protein and positively effects downstream signaling from IL-5 (33).…”

“…Earlier work has shown that a synthetic peptide containing the ICAM-1 ITIM was able to bind to Shp2 phosphatase and this interaction was phosphorylation dependent (32). Since Shp2 interacted with the GMR␤ receptor upon GM-CSF stimulation (33), we tested whether GMR␤ associated with ICAM-1 through the Shp2 adaptor molecule.…”

“…A short intracellular peptide portion of ICAM-1 contains the ITIM between aa 480 and 488 that mediates interaction with signaling proteins (32). Earlier work has shown that a synthetic peptide containing the ICAM-1 ITIM was able to bind to Shp2 phosphatase and this interaction was phosphorylation dependent (32).…”

Oxidative stress induces lipid-raft-mediated activation of Src homology 2 domain-containing protein-tyrosine phosphatase 2 in astrocytes

“…However, the enzyme is recruited to its target molecules in lipid rafts to act as either a positive or a negative regulator in several signaling pathways [12,14,17]. In view of the finding that p-SHP-2 localizes at the plasma membrane margin in a patch-like pattern (Fig.…”