Integrins are cell adhesion receptors that are evolutionary old and that play important roles during developmental and pathological processes. The integrin family is composed of 24 αβ heterodimeric members that mediate the attachment of cells to the extracellular matrix (ECM) but that also take part in specialized cell-cell interactions.
Integrins were first purified based on their matrix binding properties, and were shown to be “integral” membrane proteins that link the extracellular matrix and the intercellular cytoskeleton, thus the name “integrins”. Integrins comprise a large family of α/β heterodimeric receptors. To date, there are 18 α subunits and 8 β integrin subunits have been reported in vertebrates that form 24 heterodimers, making integrins the most diverse family of cell adhesion molecules. The study of individual α and β subunits using genetically modified mice has proven to be useful in identifying their in vivo function. In addition, deletion of β1 integrins in mice results in peri-implantation lethality and embryos fail to gastrulate. In addition, conditional deletion of β1 integrins in cartilage and skeletal muscle indicate an important role during myogenesis and chondrogenesis. Therefore, identifying which aspect(s) of integrin function regulate cytokinesis will provide a better understanding for its role during differentiation and development of multicellular organisms.
The activity of integrins is conformationally regulated. Several studies suggest that the extracellular domains of integrins can exist in various states: a bent (closed) conformation, an intermediate conformation with a closed head piece, and an extended (open) conformation. There are two well accepted mechanisms for this process: (1) inside-out and (2) outside-in integrin activation. The binding of extracellular ligands to integrins induces a conformational change resulting in a cascade of intracellular signaling events (outside-in). Alternatively, studies in cultured cells showed that binding of the ubiquitously expressed cytoskeletal protein talin, promotes integrin activation by binding to the conserved membrane-proximal NPxY motif present in the cytoplasmic domain of β1 and β3 integrins (inside-out).
Integrins are a family of heterodimeric cell adhesion receptors, which not only mediate cell adhesion to extracellular matrix proteins, but also transmit signals that are vital for anchorage-dependent cell survival, proliferation, and motility. Thus, integrins play pivotal roles in physiological processes such as wound healing, immune responses, and hemostasis. Aberrant integrin signaling is also centrally involved in the development of human diseases such as thrombosis, cancer, and autoimmune diseases, and is the target of many therapeutic agents. Therefore, understanding the molecular events in the transduction of integrin signals is important in our understanding of many biological processes and has the potential to reveal novel intervention for diseases.
Many studies have demonstrated that the integrin β tails play important roles in regulating integrin activation, integrin-ligand interactions, cell-matrix adhesion, signaling, integrin-actin cytoskeletal linkages, spreading and focal adhesion and stress fiber formation. Following activation, intracellular proteins bind the β tail and form a complex that localizes to focal adhesion sites. As an example, focal adhesion kinase (FAK) binds to the membrane-proximal region of the β subunit and functions as a major regulator of many integrin-mediated signaling pathways. FAK also functions as a scaffold protein and binds Src-family kinases (SFK), crk-associated protein (p130CAS) and paxillin, thereby contributing to the phosphorylation of FAK at other sites. In addition, SFK's recruit the adaptor protein She, which can then associate with growth factor receptor bound-2 (GRB2) and son-of-sevenless (SOS) to activate the Ras/Raf/MEK/ERK signaling pathway. Since the MEK/ERK pathway has been implicated in regulating cell proliferation, it may play an important role during cytokinesis.
The importance of the β tail in regulating integrin signaling and cell spreading along with its ability to bind proteins was demonstrated as the expression of a single subunit chimeric integrins containing the extracellular and transmembrane domains of the interleukin-2 (IL-2/tac) receptor fused to the cytoplasmic domain of various β integrin subunits. These studies revealed that clustering single subunit integrins using antibody coated magnetic beads was sufficient to trigger FAK phosphoryl ation and promote downstream signaling to p130CAS, paxillin, and Rac1.
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