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8.A.54 The Integrin (Integrin) Family 

Integrins are transmembrane receptors that mediate cell-cell and cell-extracellular matrix interactions, which regulate numerous intracellular signals and biological functions under physiological conditions. They interlink the nucleus and plasma membrane, control tumor cell growth and progression, and determine cell motility (Madrazo et al. 2017). They play important roles in cell-cell interactions, for example, promoting fusion of sperm and egg cells during mammalian fertilization (Klinovska et al. 2014). Integrin alpha-1/beta-1 is a receptor for laminin and collagen. It recognizes the proline-hydroxylated sequence G-F-P-G-E-R in collagen. They are involved in anchorage-dependent, negative regulation of EGF-stimulated cell growth.

Integrins alpha-1/beta-1, alpha-2/beta-1, alpha-10/beta-1 and alpha-11/beta-1 are receptors for collagen. Integrins alpha-1/beta-1 and alpha-2/beta-2 recognize the proline-hydroxylated sequence G-F-P-G-E-R in collagen. Integrins alpha-2/beta-1, alpha-3/beta-1, alpha-4/beta-1, alpha-5/beta-1, alpha-8/beta-1, alpha-10/beta-1, alpha-11/beta-1 and alpha-V/beta-1 are receptors for fibronectin. Alpha-4/beta-1 recognizes one or more domains within the alternatively spliced CS-1 and CS-5 regions of fibronectin. Integrin alpha-5/beta-1 is a receptor for fibrinogen.

Integrin alpha-1/beta-1as well as alpha-2/beta-1, alpha-6/beta-1 and alpha-7/beta-1 are receptors for lamimin. Integrin alpha-4/beta-1 is a receptor for VCAM1. It recognizes the sequence Q-I-D-S in VCAM1. Integrin alpha-9/beta-1 is a receptor for VCAM1, cytotactin and osteopontin. It recognizes the sequence A-E-I-D-G-I-E-L in cytotactin. Integrin alpha-3/beta-1 is a receptor for epiligrin, thrombospondin and CSPG4. Alpha-3/beta-1 may mediate with LGALS3 the stimulation by CSPG4 of endothelial cells migration. Integrin alpha-V/beta-1 is a receptor for vitronectin. Beta-1 integrins recognize the sequence R-G-D in a wide array of ligands. Isoform 2 interferes with isoform 1 resulting in a dominant negative effect on cell adhesion and migration.  Integrin alpha-3/beta-1 provides a docking site for FAP (seprase) at invadopodia plasma membranes in a collagen-dependent manner and hence may participate in the adhesion, formation of invadopodia and matrix degradation processes, promoting cell invasion.

Binding of tauroursodeoxycholate (TUDC) to alpha5beta1-integrin, the beta1-integrin subunit becomes activated through a conformational change, thereby triggering integrin signaling. This triggers choleresis through a coordinated insertion of the sodium-taurocholate cotransporting polypeptide (TC# 2.A.28.1.2) into the basolateral membrane and of the bile salt export pump (TC# 3.A.1 201.2) into the canalicular membrane (Häussinger and Kordes 2017).  The integrin β1 tail plays a key role in regulating the composition and function of tight and adherens junctions that define the paracellular transport properties of terminally differentiated renal proximal tubule epithelial cells (Elias et al. 2014). 

Integrins enable cells to respond to their environment. Most integrins are heterodimers, comprising alpha and beta type I transmembrane glycoprotein chains with large extracellular domains and short cytoplasmic tails. Integrins deliver signals through multiprotein complexes at the cell surface, which interact with cytoskeletal and signaling proteins to influence gene expression, cell proliferation, morphology, and migration (Siegers 2018). 

Spatiotemporal control of integrin-mediated cell adhesion to the extracellular matrix (ECM) is critical for physiological and pathological events in multicellular organisms. Regulation of integrin adhesive function and signaling relies on the modulation of both conformation and traffic. Indeed, integrins exist in a dynamic equilibrium between a bent/closed (inactive) and an extended/open (active) conformation, respectively endowed with low and high affinity for ECM ligands (Mana et al. 2020). Detachment from the ECM and conformational inactivation are not mandatory for integrin to get endocytosed and trafficked. Specific transmembrane and cytosolic proteins involved in the control of ECM proteolytic fragment-bound active integrin internalization and recycling exist. In the complex masterplan that governs cell behavior, active integrin traffic is key to the turnover of ECM polymers and adhesion sites, the polarized secretion of endogenous ECM proteins and modifying enzymes, the propagation of motility and survival endosomal signals, and the control of cell metabolism (Mana et al. 2020).

References associated with 8.A.54 family:

Elias, B.C., S. Mathew, M.B. Srichai, R. Palamuttam, N. Bulus, G. Mernaugh, A.B. Singh, C.R. Sanders, R.C. Harris, A. Pozzi, and R. Zent. (2014). The integrin β1 subunit regulates paracellular permeability of kidney proximal tubule cells. J. Biol. Chem. 289: 8532-8544. 24509849
Häussinger, D. and C. Kordes. (2017). Mechanisms of Tauroursodeoxycholate-Mediated Hepatoprotection. Dig Dis 35: 224-231. 28249278
Klinovska, K., N. Sebkova, and K. Dvorakova-Hortova. (2014). Sperm-egg fusion: a molecular enigma of mammalian reproduction. Int J Mol Sci 15: 10652-10668. 24933635
Kommareddi, P.K., T.S. Nair, Y. Raphael, S.A. Telian, A.H. Kim, H.A. Arts, H.K. El-Kashlan, and T.E. Carey. (2007). Cochlin isoforms and their interaction with CTL2 (SLC44A2) in the inner ear. J Assoc Res Otolaryngol 8: 435-446. 17926100
Lopez-Escamez, J.A., A. Batuecas-Caletrio, and A. Bisdorff. (2018). Towards personalized medicine in Ménière''s disease. F1000Res 7:. 30430003
Madrazo, E., A.C. Conde, and J. Redondo-Muñoz. (2017). Inside the Cell: Integrins as New Governors of Nuclear Alterations? Cancers (Basel) 9:. 28684679
Mana, G., D. Valdembri, and G. Serini. (2020). Conformationally active integrin endocytosis and traffic: why, where, when and how? Biochem Soc Trans 48: 83-93. 32065228
McClure, M.J., A.N. Ramey, M. Rashid, B.D. Boyan, and Z. Schwartz. (2019). Integrin-α7 signaling regulates connexin 43, M-cadherin, and myoblast fusion. Am. J. Physiol. Cell Physiol. 316: C876-C887. 30892939
Pawar, S.C., S. Dougherty, M.E. Pennington, M.C. Demetriou, B.D. Stea, R.T. Dorr, and A.E. Cress. (2007). alpha6 integrin cleavage: sensitizing human prostate cancer to ionizing radiation. Int J Radiat Biol 83: 761-767. 18058365
Perrin, J., M. Le Coadic, A. Vernay, M. Dias, N. Gopaldass, H. Ouertatani-Sakouhi, and P. Cosson. (2015). TM9 family proteins control surface targeting of glycine-rich transmembrane domains. J Cell Sci 128: 2269-2277. 25999474
Sabetian, S., M.S. Shamsir, and M. Abu Naser. (2014). Functional features and protein network of human sperm-egg interaction. Syst Biol Reprod Med 60: 329-337. 25222562
Short, S.M., A. Derrien, R.P. Narsimhan, J. Lawler, D.E. Ingber, and B.R. Zetter. (2005). Inhibition of endothelial cell migration by thrombospondin-1 type-1 repeats is mediated by beta1 integrins. J. Cell Biol. 168: 643-653. 15716381
Siegers, G.M. (2018). Integral Roles for Integrins in γδ T Cell Function. Front Immunol 9: 521. 29593745
Tran, T., K. Ens-Blackie, E.S. Rector, G.L. Stelmack, K.D. McNeill, G. Tarone, W.T. Gerthoffer, H. Unruh, and A.J. Halayko. (2007). Laminin-binding integrin alpha7 is required for contractile phenotype expression by human airway myocytes. Am J Respir Cell Mol Biol 37: 668-680. 17641293
Zou, B., D. Wang, K. Xu, D.Y. Yuan, Z. Meng, and B. Zhang. (2019). Integrin α-5 as a potential biomarker of head and neck squamous cell carcinoma. Oncol Lett 18: 4048-4055. 31579416