Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, organization of the intracellular cytoskeleton, and movement of new receptors to the cell membrane. The presence of integrins allows rapid and flexible responses to events at the cell surface.
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. It is approved for marketing as a topical solution in India by Central Drugs Standard Control organization in 2020 under the brand name FIBREGA for chronic wounds. Fibronectin also binds to other extracellular matrix proteins such as collagen, fibrin, and heparan sulfate proteoglycans.
Angiostatin is a naturally occurring protein found in several animal species, including humans. It is an endogenous angiogenesis inhibitor. Clinical trials have been undertaken for its use in anticancer therapy.
Endostatin is a naturally occurring, 20-kDa C-terminal fragment derived from type XVIII collagen. It is reported to serve as an anti-angiogenic agent, similar to angiostatin and thrombospondin.
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms and many other signaling proteins. TGFB proteins are produced by all white blood cell lineages.
E-selectin, also known as CD62 antigen-like family member E (CD62E), endothelial-leukocyte adhesion molecule 1 (ELAM-1), or leukocyte-endothelial cell adhesion molecule 2 (LECAM2), is a selectin cell adhesion molecule expressed only on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation. In humans, E-selectin is encoded by the SELE gene.
Paxillin is a protein that in humans is encoded by the PXN gene. Paxillin is expressed at focal adhesions of non-striated cells and at costameres of striated muscle cells, and it functions to adhere cells to the extracellular matrix. Mutations in PXN as well as abnormal expression of paxillin protein has been implicated in the progression of various cancers.
Integrin-linked kinase is an enzyme that in humans is encoded by the ILK gene involved with integrin-mediated signal transduction. Mutations in ILK are associated with cardiomyopathies. It is a 59kDa protein originally identified in a yeast-two hybrid screen with integrin β1 as the bait protein. Since its discovery, ILK has been associated with multiple cellular functions including cell migration, proliferation, and adhesion.
PTK2 protein tyrosine kinase 2 (PTK2), also known as focal adhesion kinase (FAK), is a protein that, in humans, is encoded by the PTK2 gene. PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion and spreading processes. It has been shown that when FAK was blocked, breast cancer cells became less metastatic due to decreased mobility.
G protein-coupled receptor 56 also known as TM7XN1 is a protein encoded by the ADGRG1 gene. GPR56 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
Integrin beta-6 is a protein that in humans is encoded by the ITGB6 gene. It is the β6 subunit of the integrin αvβ6. Integrins are αβ heterodimeric glycoproteins which span the cell’s membrane, integrating the outside and inside of the cell. Integrins bind to specific extracellular proteins in the extracellular matrix or on other cells and subsequently transduce signals intracellularly to affect cell behaviour. One α and one β subunit associate non-covalently to form 24 unique integrins found in mammals. While some β integrin subunits partner with multiple α subunits, β6 associates exclusively with the αv subunit. Thus, the function of ITGB6 is entirely associated with the integrin αvβ6.
Neural precursor cell expressed developmentally down-regulated protein 9 (NEDD-9) is a protein that in humans is encoded by the NEDD9 gene. NEDD-9 is also known as enhancer of filamentation 1 (EF1), CRK-associated substrate-related protein (CAS-L), and Cas scaffolding protein family member 2 (CASS2). An important paralog of this gene is BCAR1.
Talin-1 is a protein that in humans is encoded by the TLN1 gene. Talin-1 is ubiquitously expressed, and is localized to costamere structures in cardiac and skeletal muscle cells, and to focal adhesions in smooth muscle and non-muscle cells. Talin-1 functions to mediate cell-cell adhesion via the linkage of integrins to the actin cytoskeleton and in the activation of integrins. Altered expression of talin-1 has been observed in patients with heart failure, however no mutations in TLN1 have been linked with specific diseases.
Angiogenesis is the process of forming new blood vessels from existing blood vessels, formed in vasculogenesis. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase domain (ADAM), a disintegrin and metalloproteinase domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.
Metastatic breast cancer, also referred to as metastases, advanced breast cancer, secondary tumors, secondaries or stage IV breast cancer, is a stage of breast cancer where the breast cancer cells have spread to distant sites beyond the axillary lymph nodes. There is no cure for metastatic breast cancer; there is no stage after IV.
David Schlaepfer is a California-born scientist known for his studies on cell migration and cancer metastasis. His early research focused on signaling by protein kinases, with a subsequent focus on the proteins that regulate the turnover of cell contacts with the extracellular matrix. In particular, Schlaepfer is well known for his studies on focal adhesion kinase (FAK).
The tumor microenvironment (TME) is the environment around a tumor, including the surrounding blood vessels, immune cells, fibroblasts, signaling molecules and the extracellular matrix (ECM). The tumor and the surrounding microenvironment are closely related and interact constantly. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.
The term Adhesome was first used by Richard Hynes to describe the complement of cell-cell and cell-matrix adhesion receptors in an organism and later expanded by Benny Geiger and co-workers to include the entire network of structural and signaling proteins involved in regulating cell-matrix adhesion.
A cancer-associated fibroblast (CAF) is a cell type within the tumor microenvironment that promotes tumorigenic features by initiating the remodelling of the extracellular matrix or by secreting cytokines. CAFs are a complex and abundant cell type within the tumour microenvironment; the number cannot decrease, as they are unable to undergo apoptosis.
Margaret Frame is Professor of Cancer Biology and Science Director of Cancer Research Centre at the University of Edinburgh. She is also Director of MRC Institute of Genetics & Molecular Medicine. She has made seminal contributions to understanding mechanisms of cell adhesion and motility. She previously served as deputy-director of the Beatson Institute in Glasgow.
