Integrin Cell Signaling Pathway Transduction

Cells respond to the mechanical and biochemical changes in extracellular matrix (ECM) through the crosstalk between integrins and the actin cytoskeleton.

Integrins are heterodimeric transmembrane receptors composed of eighteen alpha subunits and eight beta subunits that can be non-covalently assembled into 24 combinations. The integrin dimers bind to an array of different ECM molecules with overlapping binding affinities.

The specific integrin expression patterns by a cell dictate which ECM substrate the cell can bind and the composition of integrin adhesomes determines the downstream signalling events, thus the eventual cell behaviour and fate.

Integrins play an important role in cell signaling by modulating the cell signaling pathways of transmembrane protein kinases such as receptor tyrosine kinases (RTK). While the interaction between integrin and receptor tyrosine kinases originally was thought of as uni-directional and supportive, recent studies indicate that integrins have additional, multi-faceted roles in cell signaling.

Integrins can regulate the receptor tyrosine kinase signaling by recruiting specific adaptors to the plasma membrane. For example, β1c integrin recruits Gab1/Shp2 and presents Shp2 to IGF1R, resulting in dephosphorylation of the receptor. In a reverse direction, when a receptor tyrosine kinase is activated, integrins co-localise at focal adhesion with the receptor tyrosine kinases and their associated signaling molecules.

Integrin Cell Signaling Transduction Mechanisms

”Inside Out” Signaling

Integrins can mediate cell signaling transduction by two mechanisms, so called “inside out” signaling and “outside in” signaling.

Inside out signaling is the mechanism by which a cell regulates the affinity state of its integrin receptors. It is thought to involve the propagation of conformational changes from the cytoplasmic domains of integrins to the extracellular binding site in response to intracellular signaling events.

Several regions within the cytoplasmic domains of both α and β subunits have been shown to be involved in regulating the affinity state of the integrin receptor.

There is evidence that conformational changes within these regions, brought about through phosphorylation or dephosphorylation events, allow the association of other proteins that can regulate the integrin activity state.

“Outside In” Signaling

Outside in signaling mediates signals from the extracellular matrix after integrin ligation and involves regulation of many fundamental cellular processes.

It involves integrin–ligand binding and receptor clustering, with subsequent assembly of the focal adhesion plaque—a complex of cytoskeletal proteins and signaling molecules including paxillin, talin, vinculin, α-actinin, tensin, and focal adhesion kinase (FAK).

This process is dependent on the GTPase Rho A. Phosphorylated FAK can also lead to activation of the mitogen activated protein (MAP) kinase pathway, probably via Ras activation, which can then influence gene expression.

Integrin Cell Signaling Transduction Products List

Ingegrin Gene Approved Name Chromosome (human)
ITGA1 integrin subunit alpha 1 5q11.2
ITGA2 integrin subunit alpha 2 5q11.2
ITGA2B integrin subunit alpha 2b 17q21.31
ITGA3 integrin subunit alpha 3 17q21.33
ITGA4 integrin subunit alpha 4 2q31.3
ITGA5 integrin subunit alpha 5 12q13.13
ITGA6 integrin subunit alpha 6 2q31.1
ITGA7 integrin subunit alpha 7 12q13.2
ITGA8 integrin subunit alpha 8 10p13
ITGA9 integrin subunit alpha 9 3p22.2
ITGA10 integrin subunit alpha 10 1q21.1
ITGA11 integrin subunit alpha 11 15q23
ITGAD integrin subunit alpha D 16p11.2
ITGAE integrin subunit alpha E 17p13.2
ITGAL integrin subunit alpha L 16p11.2
ITGAM integrin subunit alpha M 16p11.2
ITGAV integrin subunit alpha V 2q32.1
ITGAX integrin subunit alpha X 16p11.2
ITGB1 integrin subunit beta 1 10p11.22
ITGB2 integrin subunit beta 2 21q22.3
ITGB3 integrin subunit beta 3 17q21.32
ITGB4 integrin subunit beta 4 17q25.1
ITGB5 integrin subunit beta 5 3q21.2
ITGB6 integrin subunit beta 6 2q24.2
ITGB7 integrin subunit beta 7 12q13.13
ITGB8 integrin subunit beta 8 7p21.1