cell adhesion molecules
Sunday 5 February 2006
Most adhesion proteins can be classified into four main families:
immunoglobulin family CAMs
These proteins are located in the cell membrane, where they function as receptors, or they are stored in the cytoplasm.
As receptors, CAMs can bind to similar or different molecules in other cells, providing for interaction between the same cells (homotypic interaction) or different cell types (heterotypic interaction).
Integrins bind both to matrix proteins such as fibronectin and laminin, mediating adhesiveness between cells and ECM, as well as to adhesive proteins in other cells, establishing cell-to-cell contacts. The plasma form binds to fibrin, forming the provisional blood clot that fills the space created by a wound, and serves as a substratum for ECM deposition.
These linkages, particularly for the integrins, provide a mechanism for the transmission of mechanical force and the activation of intracellular signal transduction pathways that respond to these forces. Ligand binding to integrins causes clustering of the receptors in the cell membrane and formation of focal adhesion complexes.
The cytoskeletal proteins that colocalize with integrins at the cell focal adhesion complex include talin, vinculin, and paxillin. The integrin-cytoskeleton complexes function as activated receptors and trigger signal transduction pathways, which include the MAP kinase, PKC, and PI-3 kinase pathways.
Not only is there functional overlap between integrin and growth factor receptors, but integrins and growth factor receptors interact ("cross-talk") to transmit environmental signals to the cell, which regulate cell proliferation, apoptosis, and differentiation.
β-catenin (CTNN1) links cadherins (CDHs) with α-catenin, which, in turn, connects to actin, thus completing the connection with the cytoskeleton.
Cell-to-cell interactions mediated by cadherins and catenins play a major role in regulating cell motility, proliferation, and differentiation and account for the inhibition of cell proliferation that occurs when cultured normal cells contact each other ("contact inhibition").
Free β-catenin can act independently of cadherins, functioning as a regulator of nuclear transcription factors in the Wnt signaling pathway. Mutation and altered expression of the β-catenin pathway is of major importance for cancer development, particularly in gastrointestinal and liver cancers.
In addition to the four families of adhesive proteins described below, some other secreted adhesion molecules may be mentioned because of their potential role in disease processes:
(1) SPARC (secreted protein acidic and rich in cysteine), also known as osteonectin, contributes to tissue remodeling in response to injury, and functions as an angiogenesis inhibitor;
(2) thrombospondins, a family of large multifunctional proteins, some of which, similar to SPARC, also inhibit angiogenesis;
(3) osteopontin, which regulates calcification, and can also function as a mediator of leukocyte migration by serving as a ligand for the CD44 receptor;
(4) the tenascin family (TNs), which consist of large multimeric proteins involved in morphogenesis and cell adhesion.
CAMs and signal-transduction pathways
In addition to their adhesive functions, cell-adhesion molecules modulate signal-transduction pathways by interacting with molecules such as receptor tyrosine kinases, components of the WNT signalling pathway and RHO-family GTPases.
Changes in the expression of cell-adhesion molecules affect not only the adhesive repertoire of a cell, but also its signal-transduction status. Conversely, signalling pathways can modulate the function of cell-adhesion molecules, altering the interactions between cells and their environment. These processes have a crucial role in tumour progression, in particular during invasion and metastasis.
Changes in the expression or function of cell-adhesion molecules can therefore contribute to tumour progression both by altering the adhesion status of the cell and by affecting cell signalling.
Cell-adhesion molecules of various classes and functions, including cadherins, immunoglobulin-like cell-adhesion molecules (Ig-CAMs), the hyaluronan receptor CD44 and integrins, can interact with and modulate several signalling pathways. Conversely, signalling molecules can directly affect the function of adhesion molecules (CAMs), leading to changes in cell-cell and cell-matrix interactions.
Prominent examples of adhesion defects include autoimmune diseases, or tumour invasion and metastasis and malignant transformation.