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Junctional adhesion molecule-A: functional diversity through molecular promiscuity

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Abstract

Cell adhesion molecules (CAMs) of the immunoglobulin superfamily (IgSF) regulate important processes such as cell proliferation, differentiation and morphogenesis. This activity is primarily due to their ability to initiate intracellular signaling cascades at cell–cell contact sites. Junctional adhesion molecule-A (JAM-A) is an IgSF-CAM with a short cytoplasmic tail that has no catalytic activity. Nevertheless, JAM-A is involved in a variety of biological processes. The functional diversity of JAM-A resides to a large part in a C-terminal PDZ domain binding motif which directly interacts with nine different PDZ domain-containing proteins. The molecular promiscuity of its PDZ domain motif allows JAM-A to recruit protein scaffolds to specific sites of cell–cell adhesion and to assemble signaling complexes at those sites. Here, we review the molecular characteristics of JAM-A, including its dimerization, its interaction with scaffolding proteins, and the phosphorylation of its cytoplasmic domain, and we describe how these characteristics translate into diverse biological activities.

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Abbreviations

AA:

Amino acid

AJ:

Adherens junctions

aPKC:

Atypical protein kinase C

BAR:

Bin/amphiphysin/RVS

CAR:

Coxsackie and adenovirus receptor

CASK:

Calcium/calmodulin-dependent serine protein kinase

Cdc42:

Cell division cycle 42

Csk:

C-Src kinase

EMT:

Epithelial-to-mesenchymal transition

FERM:

4.1 protein and ERM

GEF:

Guanine nucleotide exchange factor

IgSF:

Immunoglobulin superfamily

JAM:

Junctional adhesion molecule

LGL:

Lethal(2) giant larvae protein homolog

LIN:

Abnormal cell lineage protein

MAPK:

Mitogen-activated protein kinase

MUPP1:

Multiple PDZ domain protein 1

pAJs:

Primordial, spot-like adherens junctions

Pals1:

Protein associated with Lin-7

PAR:

Partitioning defective

PATJ:

Pals1-associated tight junction protein

PICK1:

Protein interacting with C kinase 1

PMCA4B:

Plasma membrane calcium-transporting ATPase 4

PDZ:

PSD95–Discs large–ZO-1

RAC1:

Ras-related C3 botulinum toxin substrate 1

RAPGEF:

Rap guanine nucleotide exchange factor

SH:

Src homology

Src:

Sarcoma

TJ:

Tight junctions

ZO:

Zonula occludens

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Acknowledgements

We wish to thank Volker Gerke for continuous support. This work is supported by grants from the German Research Foundation to K.E. (EB 160/4-2, EB 160/5-1, EXC-1003 FF-2016-01) and from the Medical Faculty of the University Münster to K.E. (IZKF Eb2/020/14).

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  1. Institute-Associated Research Group: Cell Adhesion and Cell Polarity, Institute of Medical Biochemistry, ZMBE, University of Münster, Von-Esmarch-Str. 56, 48149, Münster, Germany

    Tim Steinbacher, Daniel Kummer & Klaus Ebnet

  2. Cells-In-Motion Cluster of Excellence (EXC1003-CiM), University of Münster, Münster, Germany

    Tim Steinbacher & Klaus Ebnet

  3. Interdisciplinary Clinical Research Center (IZKF), University of Münster, Münster, Germany

    Daniel Kummer & Klaus Ebnet

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  1. Tim Steinbacher
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Correspondence to Klaus Ebnet.

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Steinbacher, T., Kummer, D. & Ebnet, K. Junctional adhesion molecule-A: functional diversity through molecular promiscuity. Cell. Mol. Life Sci. 75, 1393–1409 (2018). https://doi.org/10.1007/s00018-017-2729-0

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