signal transduction diagrams

Signaling Molecules: Roles in Differentiation and Proliferation Signaling Molecules q Receptors – Ion channel linked receptors – Enzyme-linked receptors: single pass q q intrinsic enzyme activities coupled to intracellular enzymes – G-protein coupled: 7-pass serpentine – Cytoplasmic and nuclear receptors q q Cytoplasmic transducers Nuclear targets Ion Channel Linked Receptors ! ! ! Commonly called transmitter-gated ion channels or ionotropic receptors Involved in rapid synaptic signaling Classically defined by acetylcholine (ACh) receptor at neuromuscular junction ! Nerve impulse depolarizes axon, signal travels to nerve terminal leading to opening of voltage-gated Ca2+ channels, Ca2+ flows in and ACh is released ! ACh binds receptors on muscle cells leading to opening of cation channel and Na+ flows in Receptors Associated with Enzyme Activity qY kinases: different classes – eg PDGF, FGF, insulin, EGF qY phosphatases – eg CD45 q guanylate cyclases – eg natriuretic peptide receptors q S/T kinases – TGF-β, activin and BMP q lack activity but coupled to Y-kinases Receptors with Tyrosine Kinase Activity Coupling insulin binding to multiple signal pathways Intracellular Transducers q S/T kinases – PKA, PKC, MAPK, ERK, Raf, etc q phospholipases – PLCγ q lipid kinases – PI3K, PKB/AKT Receptor Coupling q thru SH2 domains, bind to Y-phos – PLCγ, PI3K, grb2, Shc – phosphatases (PTP) q thru SH3 domains – grb2, Sos Signal Divergence, Convergence, and Cross-talk from PDGF Receptor Convergence of signals to the Ras pathway Signal divergence from insulin receptor Vasculogenesis and Angiogenesis Vasculogenesis involves formation of initial blood islands and construction of capillary networks Angiogenesis involves formation of new blood vessels Nitric Oxide (NO) signaling NO can act as a diffusible messenger Intracellular Receptors q Steroid/Thyroid hormone super-family of receptors q contain ligand and DNA binding domains q reside in cytoplasm, bind ligand then migrate to nucleus where they interact with specific DNA sequences Steroid Hormone Receptors ! Other binding proteins include: – Hsp70 – FKBP (immunophilin) – p23 ! Functions of the binding proteins are unclear – Receptor trafficking ! Binding proteins dissociate upon ligand binding Receptor-Binding Proteins APC in GI Cancers ! FAP due to germline mutations in APC ! Somatic (sporadic) mutations in the APC gene initiate colorectal malignancy ! APC mutations in 63% of colonic adenomas ! 99% of germline and 100% of sporadic APC mutations lead to truncated protein Significance of Signal Transduction to Disease: Tumorigenesis q q Cancer cells contain genetic damage many of the genes encoding signaling molecules have been shown to be capable of causing cancer if disrupted in some way APC Function ! ! ! ! APC associates with β-catenin, a protein involved in the Wnt signaling pathway APC induces β-catenin phos leading to its degradation β-catenin acts as transcription factor, induces genes like MYC β-catenin also linked to intercellular adhesion molecules, e.g E-cadherin Wnt signaling β-catenin bound in complex which includes GSK-3; this kinase phosphorylates βcatenin leading to its degradation Activation of disheveled causes inhibition of GSK-3 β-catenin builds up, is released from complex, and translocates to nucleus where it forms part of a transcription factor complex to activate gene expression Chronic Myeloid Leukemia ! CML results from a translocation between chromosomes and 22 ! Result is termed the Ph+ chromosome ! ABL gene on chromosome placed next to BRC gene on 22 results in a fusion protein bcr-abl ! abl is a non-receptor Y-kinase ! bcr is member of the Rho family of small GTPases ! ! Similar translocation occurs in ALL CML is target of Y-kinase inhibitor Glivec Non-Hodgkin’s Lymphoma ! ! ! ! ! ! 80-90% of NHL show chromosomal aberrations t(8;14) most frequent, also 1st chromosome abnormality to be molecularly characterized Also found in Burkitt lymphoma MYC on placed near immunoglobulin heavy chain gene enhancer on 14 Another common translocation is t(14;18) BCL2 gene on 18 is disrupted, bcl2 involved in control of apoptosis, disruption leads to loss of induced apoptosis ... Divergence, and Crosstalk in signal transduction pathways Signal Divergence, Convergence, and Cross-talk from PDGF Receptor Convergence of signals to the Ras pathway Signal divergence from insulin... Cell Adhesion Molecules Activation of signal transduction via cell adhesion molecules Integrin-mediated signaling through associated Tyr-PK Another example of signaling through integrins via associated... MAPK activates transcription factors Activation of STAT signaling Receptorassociated PTK is activated and phosphorylates STAT proteins (Signal Transduction and Activator of Transcription), which