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SIGNALING FROM THE CELL SURFACE TO THE NUCLEUS • PROTEIN KINASE A • PHOSPHORYLATION AND ACTIVATION OF CREB TRANSCRIPTION FACTOR • RECEPTOR SERINE KINASES - RECEPTORS FOR THE TGF-ß SUPERFAMILY • PHOSPHORYLATION AND ACTIVATION OF SMAD TRANSCRIPTION FACTORS • PARTNERING WITH OTHER TRANSCRIPTION FACTORS TO ACTIVATE TRANSCRIPTION OF SPECIFIC GENES • PROTEIN- TYROSINE KINASE RECEPTORS • RECEPTORS LINKED TO PROTEIN- TYROSINE KINASES - THE CYTOKINE RECEPTOR SUPERFAMILY • RECEPTORS LINKED TO PROTEOSOME- MEDIATED DEGRADATION OF INHIBITORS OF SPECIFIC TRANSCRIPTION FACTORS SIGNALING PATHWAYS LEADING TO ACTIVATION OF TRANSCRIPTION FACTORS AND MODULATION OF GENE EXPRESSION FOLLOWING LIGAND BINDING TO CERTAIN GS PROTEIN–LINKED RECEPTORS TGF-b: Key Roles in Controlling Cell Proliferation and Synthesis of the Extracellular Matrix THE TGF- ß SUPERFAMILY INCLUDES TGF- ß1, TGF- ß2, TGF- ß3, ACTIVIN, INHIBIN, MULLERIAN INHIBITING SUBSTANCE, TGF-b1 AND AT LEAST 16 BONE MORPHOGENETIC PROTEINS Hinck et al., (1996) Biochemistry TGF-b: Key Roles in Controlling Cell Proliferation and Synthesis of the Extracellular Matrix BIOLOGICAL FUNCTIONS OF TGF-ß INCLUDE: • INHIBITION OF CELL PROLIFERATION • INDUCES INHIBITORS OF CYCLIN - DEPENDENT KINASES • TYPE II RECEPTOR FREQUENTLY LOST OR MUTATED IN CANCERS • INDUCTION OF SYNTHESIS OF EXTRACELLULAR MATRIX PROTEINS: FIBRONECTIN, COLLAGENS, PROTEOGLYCANS • INHIBITION OF SYNTHESIS OF EXTRACELLULAR PROTEASES: COLLAGENASE, PLASMINOGEN ACTIVATOR • INDUCTION OF SYNTHESIS OF INHIBITORS OF EXTRACELLULAR PROTEASES • PROMOTION OF CELL MATRIX AND CELL- CELL ATTACHMENT Schematic diagram of formation of mature dimeric TGFb proteins from secreted monomeric TGFb precursors. TGFb SIGNALS THROUGH HETEROMERIC COMPLEXES OF TYPES I AND II SERINE/THREONINE KINASE RECEPTORS, LEADING TO PHOSPHORYLATION OF EITHER SMAD2 OR SMAD3. A COMPLEX OF ONE OF THESE PHOSPHORYLATED SMAD PROTEINS AND SMAD4 THEN TRANSLOCATES TO THE NUCLEUS, WHERE IT BINDS TO OTHER TRANSCRIPTION FACTORS TO ACTIVATE TRANSCRIPTION OF A VARIETY OF GENES THE TGFb SIGNALING PATHWAY TGF-b Type I Receptors Type II Receptors Cell Mem brane THE TGFb SIGNALING PATHWAY P P P P P Smad 3 Smad 4 Nuclear Mem brane m RNA P TFE3 PAI-1 promoter P p 15 gene (Gene encoding inhibitor of protease that degrades extracellular matrix proteins) m RNA (Gene encoding cell- cycle inhibitor) unknown transcription factors COMBINATORIAL ACTIVATION OF TRANSCRIPTION BY SMAD PROTEINS SMAD3 PROTEINS BIND ONLY TO 4 BASE PAIRS OF DNA: 5’ AGAC 3’ EACH TFE3 TRANSCRIPTION FACTOR BINDS TO A 3 BASE PAIR SEQUENCE 5’ CAC 3’ A DIMER OF TWO TFE3s BINDS TO A 6 BASE PAIR SEQUENCE 5’ CACGTG 3’ (GTG IS THE COMPLEMENT OF CAC) THUS A SEQUENCE 5’ AGACxxxCACGTG 3’ BINDS ONE SMAD3 PROTEIN AND ONE TFE3 DIMER IN A PRECISE ARRANGEMENT, ALLOWING FOR TRANSCRIPTION ACTIVATION, IN THIS CASE OF THE PAI-1 GENE. QuickTime™ and a Animation decompressor are needed to see this picture. Role of TGF-b in Human Cancer Human Diseases with Alterations in the TGF-b Signaling Pathway SIGNALING FROM THE CELL SURFACE TO THE NUCLEUS • RECEPTORS LINKED TO PROTEIN- TYROSINE KINASES - THE CYTOKINE RECEPTOR SUPERFAMILY • PHOSPHOTYROSINE RESIDUES BINDING TO SPECIFIC SH2 DOMAINS • ACTIVATION OF STAT TRANSCRIPTION FACTORS • PARTNERING OF STATs WITH OTHER TRANSCRIPTION FACTORS • TERMINATION OF SIGNALING BY ACTIVATION OF PROTEIN TYROSINE PHOSPHATASES • INHIBTION OF SIGNALING BY PROTEINS CONTAINING ONLY SH2 DOMAINS • RECEPTORS LINKED TO PROTEOSOME- MEDIATED DEGRADATION OF INHIBITORS OF CERTAIN TRANSCRIPTION FACTORS HEMATOPOIESIS EPO ACTS TO STIMULATE THE PROLIFERATION AND DIFFERENTIATION OF ERYTHROID PROGENITOR CELLS TO MATURE RED CELLS G-CSF CFU-GM Granulocytes IL-3, GM-CSF, SCF IL-6 M -CSF CFU-MEG SCF Monocytes TPO IL-3, GM-CSF CFU-GEMM Platelets BFU-E Epo SCF CFU-E Epo GM -CSF IL-3 Erythrocytes CFU-Eo Pluripotent Stem Cell IL-3, GM-CSF Eosinophils Lymphoid Progenitor ERYTHROPOIETIN (EPO) THE PROTEIN THAT CONTROLS RED BLOOD CELL PRODUCTION 165 AMINO ACIDS ~ 40% CARBOHYDRATE • PRODUCED BY THE KIDNEY IN RESPONSE TO LOW O 2 PRESSURE IN THE BLOOD • BINDS TO EPO RECEPTORS ON THE SURFACE OF ERYTHROCYTE PROGENITOR CELLS IN THE BONE MARROW • STIMULATES THESE CELLS TO DIVIDE 5 TO 7 TIMES; EACH OF THE ~30 TO 100 DAUGHTERS THEN DIFFERENTIATES INTO A RED BLOOD CELL • USED CLINICALLY TO TREAT ANEMIA CAUSED BY KIDNEY FAILURE OR BY DISEASES SUCH AS AIDS EPO REGULATES RED CELL MASS IN RESPONSE TO TISSUE HYPOXIA RED CELL MASS Tissue pO2 + Epo EPO “GENE KNOCK- OUT” MICE ARE NORMAL EXCEPT THEY HAVE NO ADULT- TYPE RED BLOOD CELLS AND DIE AT EMBRYONIC DAY 14 CYTOKINE RECEPTOR SUPERFAMILY TWO CONSERVED DISULFIDE BONDS CONSERVED Trp- Ser- Xaa- Trp -Ser SEQUENCE Extracellular Intracellular BOX 1 BINDING SITE FOR JAK NO ENZYMIC ACTIVITY IN CYTOSOLIC DOMAIN CYTOKINE RECEPTORS THAT FORM HORMONEINDUCED OR HORMONESTABILIZED HOMO-DIMERS: • ERYTHROPOIETIN (EPO) • GRANULOCYTE COLONY STIMULATING FACTOR • THROMBOPOIETIN (TPO) • PROLACTIN (PRL) • GROWTH HORMONE (GH) SALES OF EPO AND G-CSF ARE IN EXCESS OF $4 AND $2 BILLION/ YEAR, RESPECTIVELY STRUCTURE OF HUMAN GROWTH HORMONE LIKE EPO AND OTHER CYTIOKINES, GROWTH HORMONE FORMS A 4- ALPHA HELIX BUNDLE. AMINO ACIDS THAT BIND TO THE FIRST GROWTH HORMONE RECEPTOR ARE IN GREEN; THOSE THAT BIND TO THE SECOND GROWTH HORMONE RECEPTOR ARE IN BLUE STRUCTURE OF THE EXTERNAL SEGMENT OF THE HUMAN GROWTH HORMONE RECEPTOR THE PLASMA MEMBRANE IS AT THE BOTTOM OF THE FIGURE AMINO ACIDS THAT BIND GROWTH HORMONE ARE IN BLUE AMINO ACIDS THAT BIND THE SECOND MOLECULE OF GROWTH HORMONE RECEPTOR ARE IN GREEN THREE- DIMENSIONAL STRUCTURE OF THE COMPLEX OF ONE MOLECULE OF HUMAN GROWTH HORMONE AND TWO GROWTH HORMONE RECEPTORS PLASMA MEMBRANE IS AT THE BOTTOM OF THE FIGURE SIGNAL TRANSDUCTION PROTEINS THAT BIND TO THE CYTOSOLIC DOMAIN OF THE ERYTHROPOIETIN RECEPTOR JAK2 130 kDa CYTOSOLIC PROTEIN TYROSINE KINASE HOMOLOGOUS TO JAK1 AND TYK2 WIDELY EXPRESSED IN HEMATOPOIETIC CELLS AND FIBROBLASTS NO SH2 OR SH3 DOMAINS N-T ERMINAL CONSERVED PSEUDO-KINASE DOMAIN MODULATORY KINASE DOMAIN T YROSINE KINASE SHP1 68 kDa CYTOSOLIC PROTEIN TYROSINE PHOSPHATASE EXPRESSED ONLY IN HEMATOPOIETIC CELLS MUTATED IN Motheaten MICE SH2 SH2 CAT ALYTIC DOMAIN EPO TWO POSSIBLE MECHANISMS BY WHICH EPO ACTIVATES THE EPO RECEPTOR EPO- INDUCED RECEPTOR DIMERIZATION; TRANS-PHOSPHORYLATION OF JAK2 JAK 2 P JAK 2 EPO- INDUCED CONFORMATIONAL CHANGE OF DIMERIC RECEPTOR; TRANS-PHOSPHORYLATION OF JAK2 JAK 2 JAK 2 P JAK 2 JAK 2 P JAK 2 P EPO SIGNAL TRANSDUCTION BY THE EPO RECEPTOR ACTIVATED JAK2 PHOSPHORYLATES UP TO 8 TYROSINE RESIDUES ON THE CYTOSOLOC DOMAIN OF THE EPO RECEPTOR. EACH PHOSPHOTYROSINE CAN FORM THE “DOCKING SITE” FOR THE SH2 DOMAIN OF A SIGNAL TRANSDUCTION PROTEIN MODEL OF AN SH2 DOMAIN BOUND TO A SHORT TARGET PEPTIDE. IN THIS TARGET PEPTIDE, THE PHOSPHOTYROSINE (P-TYR) AND ISOLEUCINE (+3ILE) FIT INTO A TWOPRONGED SOCKET ON THE SURFACE OF THE SH2 DOMAIN. THE PHOSPHATE GROUP COVALENTLY ATTACHED TO THE TYROSINE RESIDUE IS LIGHT BLUE. P DIMERIZATION OF STAT PROTEINS LEADS TO FORMATION OF A FUNCTIONALLY ACTIVE TRANSCRIPTION FACTOR P DIMER OF STAT PROTEIN IS FUNCTIONAL TRANSCRIPTION FACTOR: MOVES INTO NUCLEUS, BINDS TO DNA, AND ACTIVATES TRANSCRIPTION OF THE BCL-X ANTIAPOPTOTIC PROTEIN AMONG OTHERS P DIMERIZATION OF STAT PROTEIN BY BINDING OF PHOSPHOTYROSINE TO THE SH2 DOMAIN ON THE PARTNER SUBUNIT STAT STAT STAT TERMINATION OF SIGNAL TRANSDUCTION BY THE EPO RECEPTOR TERMINATION OF SIGNAL TRANSDUCTION BY THE EPO RECEPTOR #2 GENERAL STRUCTURE AND ACTIVATION OF RECEPTOR TYROSINE KINASES (RTKS) AS WITH THE EPO RECEPTOR, LIGAND BINDING INDUCES A CONFORMATIONAL CHANGE THAT PROMOTES OR STABILIZES RECEPTOR DIMERS. THE KINASE ACTIVITY OF EACH SUBUNIT OF THE DIMERIC RECEPTOR INITIALLY PHOSPHORYLATES TYROSINE RESIDUES NEAR THE CATALYTIC SITE IN THE OTHER SUBUNIT, CAUSING ITS ACTIVATION. SUBSEQUENTLY, TYROSINE RESIDUES IN OTHER PARTS OF THE CYTOSOLIC DOMAIN BECOME PHOSPHORYLATED AND SERVE AS DOCKING SITES FOR SH2 DOMAINS OF SIGNALING PROTEINS Structure of the FGF FGR Receptor Complex Structures of MAP kinase in its inactive, unphosphorylated form and active, phosphorylated form Phosphorylation of MAP kinase by MEK at tyrosine 185 (pY185) and threonine 183 (pT183) leads to a marked conformational change in the phosphorylation lip (red). Cycling of the Ras protein between the inactive form with bound GDP and the active form with bound GTP Activation of Ras following binding of a ligand to a RTK Model of SH3 domain bound to a short target peptide Kinase cascade that transmits signals downstream from activated Ras protein Signaling pathways leading to activation of transcription factors and modulation of gene expression following ligand binding to RTKs Activation of protein kinase B by the PI- 3’ kinase signaling pathway (part 1). Activation of protein kinase B by the PI- 3’ kinase signaling pathway (part 2). Cleavage of PIP2 by phospholipase C (PLC) yields DAG and IP3. Elevation of cytosolic Ca2+ via the inositol-lipid signaling pathway UBIQUITIN-MEDIATED PATHWAY FOR DEGRADATION OF CELLULAR PROTEINS A CONJUGATING ENZYME CATALYZES FORMATION OF A PEPTIDE BOND BETWEEN THE SMALL PROTEIN UBIQUITIN (UB) AND THE SIDE-CHAIN –NH2 OF A LYSINE RESIDUE IN A TARGET PROTEIN. ADDITIONAL UB MOLECULES ARE ADDED, FORMING A MULTIUBIQUITIN CHAIN. THIS CHAIN DIRECTS THE TAGGED PROTEIN TO A PROTEASOME, WHICH CLEAVES THE PROTEIN INTO NUMEROUS SMALL PEPTIDE FRAGMENTS. PROTEOLYSIS OF UBIQUITINTAGGED PROTEINS OCCURS ALONG THE INNER WALL OF THE CORE. ACTIVATION OF THE TRANSCRIPTION FACTOR NF-kB MANY DIFFERENT EXTRACELLULAR SIGNALS CAN INDUCE ACTIVATION OF NF-kB; THESE SIGNALS ACTIVATE AN I-kB KINASE COMPLEX. THIS COMPLEX PHOSPHORYLATES TWO N-TERMINAL SERINE RESIDUES IN I-kB. PHOSPHORYLATED I-kB IS UBIQUITINATED AND SUBSEQUENTLY DEGRADED BY THE PROTEOSOME. REMOVAL OF I-kB UNMASKS THE NUCLEAR LOCALIZATION SITES IN BOTH THE P50 AND P65 SUBUNITS OF NF-kB. NFkB ENTERS THE NUCLEUS, BINDS TO SPECIFIC SEQUENCES IN DNA AND REGULATES TRANSCRIPTION.