Cell-cell communication mediated by the CAR subgroup of immunoglobulin cell adhesion molecules in health and disease

Abstract

The immunoglobulin superfamily represents a diverse set of cell-cell contact proteins and includes well-studied members such as NCAM1, DSCAM, L1 or the contactins which are strongly expressed in the nervous system. In this review we put our focus on the biological function of a less understood subgroup of Ig-like proteins composed of CAR (coxsackievirus and adenovirus receptor), CLMP (CAR-like membrane protein) and BT-IgSF (brain and testis specific immunoglobulin superfamily). The CAR-related proteins are type I transmembrane proteins containing an N-terminal variable (V-type) and a membrane proximal constant (C2-type) Ig domain in their extracellular region which are implicated in homotypic adhesion. They are highly expressed during embryonic development in a variety of tissues including the nervous system whereby in adult stages the protein level of CAR and CLMP decreases, only BT-IgSF expression increases within age. CAR-related proteins are concentrated at specialized cell-cell communication sites such as gap or tight junctions and are present at the plasma membrane in larger protein complexes. Considerable progress has been made on the molecular structure and interactions of CAR while research on CLMP and BT-IgSF is at an early stage. Studies on mouse mutants revealed biological functions of CAR in the heart and for CLMP in the gastrointestinal and urogenital systems. Furthermore, CAR and BT-IgSF appear to regulate synaptic function in the hippocampus.

IgSF11 regulates osteoclast differentiation through association with the scaffold protein PSD-95

“…IgSF11 shares an identical overall domain organization with a membrane-distal V-type domain and a membrane-proximal C2-type domain with coxsackievirus and adenovirus receptor (CAR), endothelial cellselective adhesion molecule (ESAM), and CAR-like membrane protein (CLMP). [25][26][27] To investigate the expression dynamics of IgSF11 during osteoclast differentiation, we generated osteoclasts in vitro from mouse bone marrow-derived monocytes (BMMs) treated with M-CSF + RANKL for up to three days and performed temporal Q-PCR-based expression analysis and western blotting. The expression of IgSF11 gradually increased during culture and peaked on day two after RANKL treatment at both message ( Fig.…”

The CAR group of Ig cell adhesion proteins–Regulators of gap junctions?

“…The Coxsackie‐ and Adenovirus Receptor (CAR) is the founder of a small and evolutionary conserved group of Ig‐like cell adhesion proteins [ 1 ] (Figure 1a). It was initially characterized as a high‐affinity receptor protein for subtypes of coxsackie‐ and adenovirus in 1997 and therefore, named Coxsackie‐ and Adenovirus receptor.…”

The cell adhesion molecule BT-IgSF is essential for a functional blood–testis barrier and male fertility in mice

“…BT-IgSF (brain-and testis-specific Ig superfamily protein, also termed IgSF11) is a transmembrane Ig-like cell adhesion molecule (IgCAM) 2 with a widespread tissue distribution that is preferentially expressed in brain and testis (1,2). BT-IgSF shares with coxsackievirus and adenovirus receptor (CAR), endothelial cell-selective adhesion molecule, and CLMP (CAR-like membrane protein) an identical overall domain organization with a membrane-distal V-type domain and a membrane-proximal C2-type domain (3). Adhesion assays with heterologous cells demonstrated that BT-IgSF promotes homotypic binding between neighboring cells similar to its related proteins CAR or CLMP (4,5).…”