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:

Aoun, L., A. Farutin, N. Garcia-Seyda, P. Nègre, M.S. Rizvi, S. Tlili, S. Song, X. Luo, M. Biarnes-Pelicot, R. Galland, J.B. Sibarita, A. Michelot, C. Hivroz, S. Rafai, M.P. Valignat, C. Misbah, and O. Theodoly. (2020). Amoeboid Swimming Is Propelled by Molecular Paddling in Lymphocytes. Biophys. J. 119: 1157-1177.

Eckes, B., M.C. Zweers, Z.G. Zhang, R. Hallinger, C. Mauch, M. Aumailley, and T. Krieg. (2006). Mechanical tension and integrin alpha 2 beta 1 regulate fibroblast functions. J Investig Dermatol Symp Proc 11: 66-72.

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.

Gullberg, D.E. and E. Lundgren-Akerlund. (2002). Collagen-binding I domain integrins--what do they do? Prog Histochem Cytochem 37: 3-54.

Häussinger, D. and C. Kordes. (2017). Mechanisms of Tauroursodeoxycholate-Mediated Hepatoprotection. Dig Dis 35: 224-231.

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.

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.

Lopez-Escamez, J.A., A. Batuecas-Caletrio, and A. Bisdorff. (2018). Towards personalized medicine in Ménière''s disease. F1000Res 7:.

Madrazo, E., A.C. Conde, and J. Redondo-Muñoz. (2017). Inside the Cell: Integrins as New Governors of Nuclear Alterations? Cancers (Basel) 9:.

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.

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.

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.

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.

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.

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.

Siegers, G.M. (2018). Integral Roles for Integrins in γδ T Cell Function. Front Immunol 9: 521.

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.

Yeh, Y.C., H.H. Lin, and M.J. Tang. (2012). A tale of two collagen receptors, integrin β1 and discoidin domain receptor 1, in epithelial cell differentiation. Am. J. Physiol. Cell Physiol. 303: C1207-1217.

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.

Examples:

TC#NameOrganismal TypeExample
8.A.54.1.1

Integrin α-1 (AITGA1) or CD49 of 1179 aas and 2 TMSs (N- and C-termini).  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. Involved in anchorage-dependent, negative regulation of EGF-stimulated cell growth.  Plays a role in sperm-egg fusion as a receptor, but not as the fusogen (Sabetian et al. 2014).

Animals

CD49 of Homo sapiens

 
8.A.54.1.2

Integrin α-6 of 1130 aas.  Integrin alpha-6/beta-1 is a receptor for laminin on platelets. Integrin alpha-6/beta-4 is a receptor for laminin in epithelial cells and it plays a critical structural role in the hemidesmosome (Pawar et al. 2007).

Animals

ITGAE of Homo sapiens

 
8.A.54.1.3

Cochlin of 550 aas and 1 N-terminal TMS, possibly with more TMSs in the rest of the protein.  Shows similarity with a protein of TC# 2.A.74.1.6 as well as 8.A.54.1.1.  binds to ZCTL2 (SLC44A2), a putative choline transporter (TC# 2.A.92.1.2) (Kommareddi et al. 2007). It may be associated with Meniere's Disease (Lopez-Escamez et al. 2018).

Cochlin of Homo sapiens

 
8.A.54.1.4

Integrin alpha5, ITGA5, of 1048 aas.  Functions with beta subunits such as beta1 (TC# 9.B.87.1.8) (Häussinger and Kordes 2017). It is a potential biomarker of head and neck squamous cell carcinoma (Zou et al. 2019). Inhibition of endothelial cell migration by thrombospondin-1 type-1 repeats is mediated by beta1 integrins (Short et al. 2005).

Integrin α5 of Homo sapiens

 
8.A.54.1.5

Integrin alpha7 of 1181 aas and 2 TMSs, N- and C-terminal. Integrin alpha-7/beta-1 is the primary laminin receptor on skeletal myoblasts and adult myofibers (Tran et al. 2007). Signaling via this protein regulates connexin 43, M-cadherin, and myoblast fusion (McClure et al. 2019).

 

Integrin α7 of Homo sapiens

 
8.A.54.1.6

Transmembrane integrin α-L, ITGAL, of 1170 aas and 2 TMSs, N- and C-terminal.  These proteins may play a role in amoeboid swimming, propelled by molecular paddling in lymphocytes (Aoun et al. 2020). Leukocytes can swim, and efficient propulsion is by a rearward and inhomogeneous treadmilling of the cell external membrane. Thus, a molecular paddling by transmembrane proteins linked to and advected by the actin cortex is responsible for motility, whereas freely diffusing transmembrane proteins hinder swimming. Continuous paddling is enabled by a combination of external treadmilling and selective recycling by internal vesicular transport of cortex-bound transmembrane proteins (Aoun et al. 2020).

ITGAL of Homo sapiens

 
8.A.54.1.7

Integrin alpha-11, α-11, α11, of 1188 aas and 4 TMSs, one N-terminal, two close to each other in a central location in the protein, and one C-terminal. It is a receptor for collagen (Gullberg and Lundgren-Akerlund 2002). Mechanical tension and integrin beta-1 regulate fibroblast functions (Eckes et al. 2006). Cells contain at least two types of collagen receptors: integrins and discoidin domain receptors (DDRs) (Yeh et al. 2012).

Integrin α11 of Homo sapiens

 
Examples:

TC#NameOrganismal TypeExample