[HTML][HTML] Switched at birth: a new family for PECAM-1

PJ Newman - The Journal of clinical investigation, 1999 - Am Soc Clin Investig
The Journal of clinical investigation, 1999Am Soc Clin Investig
ITIMs are identifiable by the consensus sequence L/I/V/S–x–Y–x–x–L/V and have been
found to exist alone or in pairs within the cytoplasmic domain of an increasingly recognized
number of inhibitory receptors. For example, the inhibitory Fcγ receptor, FcγRIIb, harbors a
single ITIM within its cytoplasmic domain and signals predominantly through SHIP, an
inositol phosphatase that binds to the ITIM via its single amino-terminal SH2 domain. On the
other hand, Ig-ITIM family members that bind SHP-1 and SHP-2 most commonly contain two …
ITIMs are identifiable by the consensus sequence L/I/V/S–x–Y–x–x–L/V and have been found to exist alone or in pairs within the cytoplasmic domain of an increasingly recognized number of inhibitory receptors. For example, the inhibitory Fcγ receptor, FcγRIIb, harbors a single ITIM within its cytoplasmic domain and signals predominantly through SHIP, an inositol phosphatase that binds to the ITIM via its single amino-terminal SH2 domain. On the other hand, Ig-ITIM family members that bind SHP-1 and SHP-2 most commonly contain two or more ITIMs separated by at least 20 residues (50 Ć) each—a feature that no doubt contributes specificity to their recruitment and activation of these tandem SH2 domain–containing protein-tyrosine phosphatases (5). The distance separating ITIMs is in sharp contrast to the much shorter spacing between the bisphosphotyrosyl sequences present in immunoreceptor tyrosine–based activation motifs (ITAMs; consensus= Y-xx-L-x6–8-Y-xx-L), which are located within the cytoplasmic domains of stimulatory receptors such as T-cell receptor ζ chain, the Fc receptor γ chain (a 14-kDa signaling subunit that is associated with FcγRI, FcγRIII, FcεRI and platelet GPVI), all three CD3 subunits (ε, γ, and δ), the Igα/Igβ dimer that is associated with the ” chain of the B-cell receptor, and FcγRIIa (for recent reviews of the biology of ITAMs, see refs. 6 and 7). As a consequence of the close proximity of their phosphotyrosine residues, ITAMs appear to have a much higher affinity for the SH2 domains of protein-tyrosine kinases like ZAP-70, Syk, and phosphatidylinositol-3-kinase (8) than they do for the more widely spaced SH2 domains of protein-tyrosine phosphatases (5). This fact has only been appreciated of late, however, resulting in the inadvertent assignment of a number of proteins containing canonical ITIMs to the ITAM family of stimulatory receptors (9–11).
PECAM-1 appears to be one such example. Several years ago, Modderman et al.(12) found that PECAM-1 could become phosphorylated on tyrosine residues after treatment of platelets with pervanadate, a protein-tyrosine phosphatase inhibitor. Subsequently, Jackson et al.(13, 14) showed that two specific tyrosine residues, Y663 and Y686, located within the 118–amino acid PECAM-1 cytoplasmic domain, formed a specific docking site for the proteintyrosine phosphatase, SHP-2, and that this signaling molecule bound avidly to PECAM-1 after platelet aggregation. This has since been confirmed by several investigators (15, 16), and the number of cellular activation events that can lead to PECAM-1 tyrosine phosphorylation and SHP-2 binding has been expanded to include shear (17) or oxidative (18) stress, osmotic shock (17), exposure to lysophosphatidyl choline (19), and monoclonal antibody–induced cross-linking of the T-cell receptor (20), the Fcε receptor (20), or PECAM-1 itself (21). Thus, PECAM-1 appears to fulfill one of the criteria established for inclusion in the Ig-ITIM family (3): it recruits one or more SH2 domain–containing phosphatases after phosphorylation. In addition, the paired ITIMs within its cytoplasmic domain are remarkably similar to those present in other well-established members of the Ig-ITIM family (Fig. 1 and Table 2). Taken together, it would appear that PECAM-1 is, in fact, a member of the Ig-ITIM family, and may not necessarily have cell adhesion as its primary function after all. Rather, like other members of this family, PECAM-1 may function as an inhibitory receptor, serving to moderate or attenuate tyrosine kinase–mediated signaling pathways, or to set thresholds for cellular activation in the vascular cells that express it. Further support for inclusion of …
The Journal of Clinical Investigation