Signal transduction by Cell-Cell and Cell-Matrix contacts

Signal transduction by Cell-Cell and Cell-Matrix contacts - Integrins as central adhesion receptors - - Focal Adhesion Kinase (FAK) as a central signal molecule -

Structure of Cell/Cell and Cell/Matrix contacts

Regulation of cell functions by cell-cell and cell-matrix contacts Cell functions: - connection to other cells and to the extracellular matrix, formation of tissues - cell shape and polarisation - organisation of the cytosceleton - proliferation - survival - differentiation Cell 1 Cell 3

Wich Cell adhesion proteins are in Cell-Cell and Cell-Matrix interactions involved?

Cell Adesion molecules (CAMs) involved in Cell-Cell and Cell-Matrix contacts 20 100 >12 Cadherins: specific for formation of Cell-Cell contacts - E-Cadherin: non neuronal Epithelials - N-Cadherin: neuronal Epithelials - formation of homodimers - greatest diversity ind the brain - Ca2+-dependent ( useful in cell culture!!)

Cell adesion molecules (CAMs) involved in Cell-Cell and Cell-Matrix contacts 20 100 >12 N-CAMs: specific for Cell-Cell contacts in neuronal cells - alternative splicing of one gene - homophilic interaction - Ca2+-independent binding

Cell adesion molecules (CAMs) involved in Cell-Cell and Cell-Matrix contacts 20 100 >12 Selectins: involved in Extravasation (entry of leukocytes in tissues)

Cell adesion molecules (CAMs) involved in Cell-Cell and Cell-Matrix contacts 20 100 >12 Integrins: involved in the formation of Cell-Matrix contacts

Which proteins form the extracellular matrix and which interacts with integrins?

Collagen Structure of the extracellular matrix 2 main componets of macro molecules: 1. Proteoglycans: - main carbohydrate part, build hydrate gel - free diffusion of nutriants - fom the base of extracellular matrix - fibre proteins are embeded in the proteoglycan gel 2. Fibre proteins: 2.a Structure protein (Collagens)

2. Fibre proteins:2.a Strukture proteins (Collagens) Collagen - unsoluble main protein of the ECM an the connective tissue - formed by a triple-helix by Gly-Pro-X repeats

2.b Adhesion proteins (z.b. Laminin, Fibronectin) - big multiadhesion proteins with a lot of binding sites Fibronectin Functions: Cell shape, organisation of the cytosceleton, wound healing Structure: Dimer of two similar protein chains, connected by S-S bridges Integrin-Binding: enhanced by EDA and EDB domains

Laminin - together with collagen IV the main protein of the basal lamina - Heterotrimer - multiadhesion protein - multiple binding sites

Wich integris exist and what is the structure?

Structure of integrins Membrane which transform Cell-Matrix contacts into signal transduction - Hetrodimer proteins (a- und ß-chain) - 16 a-ue and 8 ß-UE - different combinations possible - 22 different heterodimers are known - different ligand specificity

Integrins and their ligands subunits Ligands (ECM), (Cell-Cell) (soluble) ß1 a1 Collagen, Laminin ß1 a2 Collagen, Laminin ß1 a3 Fibronectin, Laminin ß1 a4 Fibronectin, vcam ß1 a5 Fibronectin ß1 a6 Laminin ß1 a7 Laminin ß1 av Fibronectin, Vitronectin ß2 al icam-1, icam-2, ß2 am Fibrinogen, icam-1, C3b ß2 ax Fibrinogen, C3b ß3 aiib Fibrinogen, Fibronectin, Vitronectin ß4 a6 CLCA1/2 (Ca2+-sensitive Cl-chanel)

Structure of Integrins - Hetrodimer proteins (a- und ß-chain) - 16 a-ue and 8 ß-UE - different combinations possible - 22 different heterodimers are known - different ligand specificity - 1 transmembrane domain - cytoplasmatic domain contacts the cytosceleton and intracellular domains of other proteins - no own signal transduction

Which signals were mediated by integrins and which signal molecules are involved?

Integrin-modulated Integrin-modulierte signal Signaltransduktionswege transduction pathways

Focal Adhesion Kinase (FAK) central signal molecule nof the integrin-mediated signal transduction

Focal Adhesion Kinase (FAK) - localized with integrins in focal adhesion points Name

Focal Adhesion Kinase (FAK) - 120 kda "non-receptor" tyrosine kinase - highly conseved in different species (Human to Frog) - essential signal molecule FAK (-/-) mice are lethal - Binding of integrins by the N-terminal domain (HypI) or the adaptor protein Talin (Hyp II)

Focal Adhesion Kinase (FAK) - 120 kda "non-receptor" Tyrosinkinase - ca be activated by integrins, growth factors and the GTPase Rho - activation in focal adhesion points leads to an activating autophosphorylation at Y397 - Y397 phosphorylated FAK can be phosphorylated at other tyrosine residues (Src) - contains no own SH2- or SH3-Domains - Signaltransduktion is mediated by binding to other proteins with SH2-Domains

Focal Adhesion Kinase (FAK) -120 kda "non-receptor" Tyrosinkinase - ca be activated by integrins, growth factors and the GTPase Rho - activation in focal adhesion points leads to an activating autophosphorylation at Y397 - Y397 phosphorylated FAK can be phosphorylated at other tyrosine residues (Src) - contains no own SH2- or SH3-Domains - Signaltransduktion is mediated by binding to other proteins with SH2-Domains Src-K, PI3K und Grb (ERK) Proliferation Protection for Apoptosis p130cas, Paxillin, Talin Cytosceleton

Focal Adhesion Kinase (FAK) - Signal transduction by binding of SH2-adaptor proteins Interaction of ECM/Integrin and FAK

Focal Adhesion Kinase (FAK) - Signal transduction by binding of SH2-adaptor proteins Interaction of ECM/Integrin and FAK Tyrosine-Autophosphoryation after Integrin-Activation

Focal Adhesion Kinase (FAK) - Signal transduction by binding of SH2-adaptor proteina Interaction of ECM/Integrin and FAK Tyrosine-Autophosphorylation after Integrin-activation Aktivierte Signalmoleküle Interaction with Adaptor proteins

Focal Adhesion Kinase (FAK) - Signal transduction by binding of SH2-adaptor proteins Interaction of ECM/Integrin and FAK Tyrosine-autophosphorylation after Integrin-activation Activated signal molecules Interaction with adaptor proteins

Focal Adhesion Kinase (FAK) - central switch of Integrin-dependet signal transduction