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Structural and Functional Aspects of Β1 Integrin Signalling

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Structural and Functional Aspects of Β1 Integrin Signalling Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 136 Structural and Functional Aspects of β1 Integrin Signalling STINA NILSSON ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 UPPSALA ISBN 91-554-6529-3 2006 urn:nbn:se:uu:diva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o my family! List of Papers This thesis is based on the following papers, referred to in the text by their roman numerals: I Nilsson S, Kaniowska D, Brakebusch C, Fässler R, Johansson S. (2006) Threonine 788 in integrin subunit E1 regulates integrin activation. Exp Cell Res. April;312(6):844-853 II Velling T, Nilsson S, Stefansson A, Johansson S. (2004) E1- Integrins induce phosphorylation of Akt on serine 473 independ- ently of focal adhesion kinase and Src family kinases. EMBO Rep. Sep;5(9):901-5 III Nilsson S, Wärmegård B, Velling T, Johansson S. (2006) Activa- tion of Erk downstream of E1 integrins independently of FAK and ShcA. Manuscript Reprints were made with permission from the publishers. Front cover: Light microscopy image of E1A-expressing GD25 cells in culture. Contents Background...................................................................................................11 Integrins....................................................................................................11 Integrin family of receptors .................................................................11 Integrin ligands....................................................................................14 Integrin structure..................................................................................16 The extracellular domain ................................................................16 The transmembrane domain............................................................17 The cytoplasmic domain .................................................................18 Integrin activation – inside-out and back in again...................................18 Inside-out signalling ............................................................................18 Integrin extracellular conformation.................................................18 Integrin transmembrane and intracellular conformation.................20 Talin dependent integrin activation.................................................22 Regulation of integrin activation.....................................................23 Outside-in signalling............................................................................27 Clustering of integrin receptors.......................................................27 Modulation of integrin cytoplasmic interactions ............................27 Focal adhesion sites – protein ensembles with inositol guest stars .........29 Molecular components of focal adhesion sites....................................29 Cytoskeletal proteins.......................................................................30 Signalling proteins and their regulators ..........................................32 Signalling lipids and their regulators ..............................................38 Adhesion dependent and integrin regulated cell functions.......................40 Spreading and organisation of the actin cytoskeleton .........................41 Migration & integrin cell surface recycling.........................................41 Survival................................................................................................42 Crosstalk with other cell surface receptors...............................................43 Present investigation .....................................................................................44 Aims of thesis...........................................................................................44 Results and Discussion.............................................................................44 Integrin activation – depending on common features of E subunits? .44 Paper I – Extracellular activity of E1 integrins is regulated by the intracellular residue threonine 788..................................................45 E1 mediated signalling – relying on activation of the FAK/Src complex?..............................................................................................46 Paper II – FAK and PI3K activation as two parallel key events.....47 Paper III – Adhesion via E1 integrins controls activation of Erk at several checkpoints, with and without FAK involvement ..............48 Future Perspectives .......................................................................................50 Concluding remarks .................................................................................51 Acknowledgement ........................................................................................52 References.....................................................................................................54 Abbreviations Cas Crk-associated substrate Csk C-terminal Src kinase ECM Extracellular matrix ER Endoplasmic reticulum Erk1/2 Extracellular signal-regulated kinase 1 and 2 FAK Focal Adhesion Kinase FERM Band 4.1, Ezrin, Radixin, Moesin GAP GTPase-activating protein GEF Guanine nucleotide exchange factor GFR Growth factor receptor Grb2/7 Growth-factor-receptor-bound protein 2 and 7 ICAP-1 Integrin cytoplasmic domain-associated protein 1 ILK Integrin-linked kinase JNK c-Jun NH2-terminal kinase MAPK Mitogen-activated protein kinase PAK p21-activated kinase PDK1 3-phosphoinositide-dependent protein kinase 1 PH Plextrin Homology PI3K Phosphatidylinositol-3-kinase PIP2 PI(4,5)P2 or phosphatidylinositol-4,5-bisphosphate PIP3 PI(3,4,5)P2 or phosphatidylinositol-3,4,5-trisphosphate PIPK-I Phosphatidylinositol phosphate kinase type I PKB/Akt Protein kinase B / Akt PKC Protein kinase C PP2A/B Protein phosphatase 2A and 2B PTB Protein tyrosine binding PTEN Phosphatase and Tensin homologue deleted on chromosome 10 PTP-PEST Protein tyrosine phosphatase-proline, glutamate, serine, and threonine se- quences PYK2 Proline-rich tyrosine kinase 2 RGD Arginine-Glycine-Aspartic acid RPTPD Receptor protein tyrosine phosphatase D S/T Serine/threonine SAPK Stress-activated protein tyrosine kinase SH2 Src homology 2 SH3 Src homology 3 Shc Src-homology containing protein SHIP1/2 SH2-containing inositol 5-phosphatase 1 and 2 SHP1/2 SH2-domain-containing protein tyrosine phosphatase 1 and 2 Sos Son of sevenless TM Transmembrane Background Cell adhesion molecules make cells stick together into multi-cellular tissues and organisms. They also provide means for the cell to communicate with its surroundings. Cell adhesion plays a critical role both in normal processes such as embryonic development and healing of wounds as well as in patho- logical processes like tumour cell invasion and metastasis, thrombosis, and inflammation [1, 2]. Most of the cell surface receptors that mediate adhesion can be grouped into four protein families: cadherins, immunoglobulin superfamily members, selectins, and integrins (reviewed in [3]). Integrins primarily mediate interac- tions of cells with components of the extracellular matrix (ECM) such as fibronectin, vitronectin, laminins, and collagens. Attachment of cells to the matrix can affect the cells in a number of ways; the response of the cell de- pends on the type of cell involved, their state at the moment and the specific make-up of the matrix. Together with signals arising from receptors for soluble growth factors integrins enforce a cellular decision on what biologi- cal action to take, be it attachment, movement, death or differentiation. The wide range of actions in the cell, under the influence of integrins, obviously requires a large set of players and a fine-tuned control. Integrins Integrin family of receptors During the 1980’s this family of transmembrane (TM) glycoproteins were identified and named “integrins” in recognition of their importance to struc- tural integrity of cells and tissues as well as to denote their role as an integral membrane complex associating the exterior protein network with the cells interior cytoskeletal network across the plasma membrane [2, 4]. Integrin receptors act as heterodimeric non-covalent complexes formed by one D- and one E-subunit. Today, 18 D- and 8 E-subunits have been de- scribed in mammals and together they form 24 known
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