Integrin signaling revisited

Adhesion to the extracellular matrix (ECM) is a crucial regulator of cell function, and it is now well established that signaling by integrins mediates many of these effects. Ten years of research has seen integrin signaling advance on many fronts towards a molecular understanding of the control mechanisms. Most striking is the merger with studies of other receptors, the cytoskeleton and mechanical forces within the general field of signaling networks.     

Systems biology: where it's at in 2005

A report on the joint Keystone Symposia on Systems and Biology and Proteomics and Bioinformatics, Keystone, USA, 8-13 April 2005.     

Systems biology: where it's at in 2005

A report on the joint Keystone Symposia on Systems and Biology and Proteomics and Bioinformatics, Keystone, USA, 8-13 April 2005.     

Integrin signaling to the actin cytoskeleton

Integrin engagement stimulates the activity of numerous signaling molecules, including the Rho family of GTPases, tyrosine phosphatases, cAMP-dependent protein kinase and protein kinase C, and stimulates production of PtdIns(4,5)P2. Integrins promote actin assembly via the recruitment of molecules that directly activate the actin polymerization machinery or physically link it to sites of cell adhesion.     

Proteome analysis: I. Gene products are where the biological action is

Two-dimensional electrophoresis has rapidly become the method of choice for resolving complex mixtures of proteins. Since the technique was pioneered in 1975, 2-D gel methods have undergone a series of enhancements to optimize resolution and reproducibility. Recent improvements in the sensitivity of mass spectrometry have allowed the direct identification of polypeptides from 2-D gels by a procedure termed “mass profiling”. In combination, these two techniques have made possible the characterization of the complete collection of gene products, or proteome, of an organism. Proteomes are increasingly being documented as interactive informational databases available on the World Wide Web (WWW). This availability of organismic global protein patterns will no doubt be an invaluable resource aiding the discovery of diagnostic and therapeutic disease markers.     

Integrin structures and conformational signaling

Integrins are cell adhesion molecules that play critical roles in development, wound healing, hemostasis, immunity and cancer. Advances in the past two years have shed light on the structural basis for integrin regulation and signaling, especially on how global conformational changes between bent and extended conformations relate to the inter-domain and intra-domain shape shifting that regulates affinity for ligand. The downward movements of the C-terminal helices of the alpha I and beta I domains and the swing-out of the hybrid domain play pivotal roles in integrin conformational signaling. Experiments have also shown that integrins transmit bidirectional signals across the plasma membrane by coupling extracellular conformational change with an unclasping and separation of the alpha and beta transmembrane and cytoplasmic domains.     

Integrin inside-out signaling and the immunological synapse

Integrins dynamically equilibrate between three conformational states on cell surfaces. A bent conformation has a closed headpiece. Two extended conformations contain either a closed or an open headpiece. Headpiece opening involves hybrid domain swing-out and a 70 ? separation at the integrin knees, which is conveyed by allostery from the hybrid-proximal end of the βI domain to a 3 ? rearrangement of the ligand-binding site at the opposite end of the βI domain. Both bent-closed and extended-closed integrins have low affinity, whereas extended-open integrin affinity is 10(3) to 10(4) higher. Integrin-mediated adhesion requires the extended-open conformation, which in physiological contexts is stabilized by post-ligand binding events. Integrins thus discriminate between substrate-bound and soluble ligands. Analysis of LFA-1-ICAM-1 interactions in the immunological synapse suggests that bond lifetimes are on the order of seconds, which is consistent with high affinity interactions subjected to cytoskeletal forces that increase the dissociation rate. LFA-1 βI domain antagonists abrogate function in the immunological synapse, further supporting a critical role for high affinity LFA-1.     

Home is where the heart is: via the FROUNT

In this issue of Cell Stem Cell, Belema-Bedada et al. (2008) describe a novel mechanism by which bone marrow-derived adult mesenchymal stem cells migrate to sites of damaged heart tissue. This process is dependent on the intracellular adaptor molecule FROUNT, which interacts with the chemokine receptor CCR2.     

Integrin signaling in skeletal development and function

Integrins are cell surface receptors that connect extracellular matrix (ECM) components to the actin cytoskeleton and transmit chemical and mechanical signals into the cells through adhesion complexes. Integrin‐activated downstream pathways have been implicated in the regulation of various cellular functions, including proliferation, survival, migration, and differentiation. Integrin‐based attachment to the matrix plays a central role in development, tissue morphogenesis, adult tissue homeostasis, remodeling and repair, and disturbance of the ECM‐integrin‐cytoskeleton signaling axis often results in diseases and tissue dysfunction. Increasing amount of in vitro and in vivo evidences suggest that integrins are pivotal for proper development, function, and regeneration of skeletal tissues. In this paper, we will summarize and discuss the role of integrins in skeletogenesis and their influence on the physiology and pathophysiology of cartilage, bone, and tendon. Birth Defects Research (Part C) 102:13–36, 2014. © 2014 Wiley Periodicals, Inc.     

Integrin function: molecular hierarchies of cytoskeletal and signaling molecules

Integrin receptors play important roles in organizing the actin- containing cytoskeleton and in signal transduction from the extracellular matrix. The initial steps in integrin function can be analyzed experimentally using beads coated with ligands or anti- integrin antibodies to trigger rapid focal transmembrane responses. A hierarchy of transmembrane actions was identified in this study. Simple integrin aggregation triggered localized transmembrane accumulation of 20 signal transduction molecules, including RhoA, Rac1, Ras, Raf, MEK, ERK, and JNK. In contrast, out of eight cytoskeletal molecules tested, only tensin coaccumulated. Integrin aggregation alone was also sufficient to induce rapid activation of the JNK pathway, with kinetics of activation different from those of ERK. The tyrosine kinase inhibitors herbimycin A or genistein blocked both the accumulation of 19 out of 20 signal transduction molecules and JNK- and ERK-mediated signaling. Cytochalasin D had identical effects, whereas three other tyrosine kinase inhibitors did not. The sole exception among signaling molecules was the kinase pp125FAK which continued to coaggregate with alpha 5 beta 1 integrins even in the presence of these inhibitors. Tyrosine kinase inhibition also failed to block the ability of ligand occupancy plus integrin aggregation to trigger transmembrane accumulation of the three cytoskeletal molecules talin, alpha-actinin, and vinculin; these molecules accumulated even in the presence of cytochalasin D. However, it was necessary to fulfill all four conditions, i.e., integrin aggregation, integrin occupancy, tyrosine kinase activity, and actin cytoskeletal integrity, to achieve integrin- mediated focal accumulation of other cytoskeletal molecules including F- actin and paxillin. Integrins therefore mediate a transmembrane hierarchy of molecular responses.     

Integrin tyrosine phosphorylation in platelet signaling.

The beta 3 integrin cytoplasmic tyrosine (ICY) motif of alpha IIb beta 3 becomes tyrosine phosphorylated during platelet aggregation, causing Shc and myosin to interact with the beta-integrin cytoplasmic domain. Platelets from mice lacking beta 3 ICY motif tyrosines formed defective aggregates and poorly retracted clots, establishing integrin tyrosine phosphorylation as a key mediator of beta 3-integrin signals.