An alternatively spliced isoform of PECAM-1 is expressed at high levels in human and murine tissues, and suggests a novel role for the C-terminus of PECAM-1 in cytoprotective signaling

Abstract

histiocytic lymphoma cell lines. Furthermore, murine platelets and lung lysates demonstrated abundant amounts of exon-15-deficient PECAM-1. Functional studies revealed that Δ15 PECAM-1 retains both its homophilic binding capacity and its ability to signal by means of its immunoreceptor tyrosine-based inhibitory motif (ITIM) domains. Δ15 PECAM-1 was unable, however, to protect against apoptosis induced by overexpression of Bax or treatment with the chemotherapy agent etoposide. These studies suggest a novel role for the PECAM-1 C-terminus in cytoprotective signaling and highlight a need for further characterization of expression of PECAM-1 isoforms in normal and malignant tissues.

Relative contribution of PECAM-1 adhesion and signaling to the maintenance of vascular integrity

“…The inability of K89A PECAM-1 to become concentrated at endothelial cell-cell junctions (supplementary material Fig. S1) (Bergom et al, 2008;Sun et al, 2000), probably contributes to the inefficiency with which it is able to maintain or restore vascular barrier integrity, and confirms the importance of PECAM-1-PECAM-1 homophilic interactions in controlling both the subcellular location and vascular function of this adhesion and signaling receptor. Because engagement of PECAM-1 results in activation of integrin on leukocytes (Berman et al, 1996;Berman and Muller, 1995;Dangerfield et (Varon et al, 1998) and endothelial cells (Chiba et al, 1999), and because integrins enable endothelial cells to bind to extracellular matrix proteins at focal adhesions, which are crucial determinants of cell shape and permeability (Mehta and Malik, 2006), it will be interesting in future studies to determine whether integrin activation downstream of homophilic PECAM-1 engagement has a role in PECAM-1-mediated maintenance of vascular barrier integrity.…”

“…The extracellular domain of PECAM-1 is comprised of six Ig-like homology domains, followed by a 19-residue transmembrane domain and a 118-residue cytoplasmic tail (Newman et al, 1990). N-terminal extracellular Ig domain-1 contains residues that are important for mediating homophilic PECAM-1-PECAM-1 interactions that direct PECAM-1 to cell-cell junctions (Bergom et al, 2008;Newton et al, 1997;Sun et al, 2000;Sun et al, 1996), whereas Cys595, which lies immediately inside the plasma membrane, has been shown to become post-translationally palmitoylated and targets PECAM-1 to membrane microdomains, where it regulates both cell signaling and apoptosis (Gratzinger et al, 2003;Lee et al, 2006;Sardjono et al, 2006). The PECAM-1 cytoplasmic domain contains two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) centered around Tyr663 and Tyr686 that become phosphorylated in response to a variety of cellular activation events, after which they are able to recruit a number of Src homology 2 (SH2) domain-containing cytosolic signaling molecules, the best known of which is the protein-tyrosine phosphatase SHP-2 (Newman and Newman, 2003).…”

Preeclampsia Does Not Alter Vascular Growth and Expression of CD31 and Vascular Endothelial Cadherin in Human Placentas

“…CD31 contains 16 exons encoding a 5'-untranslated region and the signal peptide, an extracellular domain, a transmembrane domain, and a cytoplasmic domain, the latter of which is the major functional domain of CD31 (Newman and Newman 2003). The cytoplasmic domain of CD31 (exons 9-16) can undergo alternative splicing, resulting in different isoforms (Bergom et al 2008;Dejana and Giampietro 2012;DeLisser et al 1994;Newman and Newman 2003;Wang et al 2003). Among these isoforms, the full-length CD31 is the predominant form expressed in humans, whereas CD31 without exons 14 and 15 is the major form expressed in mice (Privratsky and Newman 2014).…”

“…Among these isoforms, the full-length CD31 is the predominant form expressed in humans, whereas CD31 without exons 14 and 15 is the major form expressed in mice (Privratsky and Newman 2014). The alternatively spliced forms of CD31 may have different cellular and tissue distributions and altered cellular functions (Bergom et al 2008;Newman 1997, Newman andNewman 2003). VE-Cad is an endothelial-specific adhesion protein that is located at junctions between endothelial cells and also serves as an endothelial marker (Lampugnani et al 1992;Vestweber 2008).…”

Proteinase 3 Contributes to Transendothelial Migration of NB1-Positive Neutrophils

“…PECAM-1 is a 130 kDa type I transmembrane glycoprotein composed of six extracellular immunoglobulin (Ig)-like homology domains, a 19-residue transmembrane domain and a 118 residue cytoplasmic tail (1). Endothelial cells express approximately 1–2 × 10 6 copies/cell (2) and homophilic trans-interactions between PECAM-1 Ig domains 1 and 2 localize this molecule to endothelial cell junctions (3–6) where it plays an important role in maintaining vascular integrity (7,8). Neutrophils and monocytes express approximately 50,000 copies of PECAM-1 on their surface, and antibodies against Ig-domain 1 and 2 of leukocyte or endothelial cell PECAM-1 have been shown to significantly inhibit leukocyte transmigration in vitro (9) and in vivo (10).…”