Module 29: Catalytic Receptors PDF

Slide 2 ------- Catalytic Receptors\ 1. Receptors with intrinsic protein tyrosine kinase activity: receptor tyrosine kinases (RTKs):\ catalyze the transfer of the γ phosphate of ATP to hydroxyl groups of tyrosines on target proteins\ control cell cycle, migration, metabolism, survival, prolifer...

Slide 2 ------- Catalytic Receptors\ 1. Receptors with intrinsic protein tyrosine kinase activity: receptor tyrosine kinases (RTKs):\ catalyze the transfer of the γ phosphate of ATP to hydroxyl groups of tyrosines on target proteins\ control cell cycle, migration, metabolism, survival, proliferation, and differentiation\ 2. Receptors associated with enzymes:\ do not contain an intrinsic protein tyrosine kinase activity\ their cytoplasmic domains interact with non-receptor tyrosine kinases\ 3. Receptor threonine/serine kinases (RTSK):\ heterodimeric functional units\ with intrinsic serine/threonine protein kinase activity\ 4. Receptor tyrosine phosphatases (RTP):\ lack cognate ligands\ might be triggered by events such as cell-to-cell contact\ 5. Guanylyl cyclases of the natriuretic peptide receptor family Tyrosine Kinase - Associated Receptors -------------------------------------- ligands: cytokines, growth factors, some hormones\ the receptors associate non-covalently with cytoplasmic tyrosine kinases (e.g., JAKs)\ ligand binding induces the receptor chains to oligomerize or reorients the chains in a preformed oligomer\ this rearrangement brings the associated cytoplasmic tyrosine kinases close together to cross-phosphorylate each other and increase their activity Cytokines --------- low-molecular weight proteins or glycoproteins secreted by immune cells and other cells\ over 200 cytokines, classified according to their function as interleukins, interferons, chemokines, etc.\ part of the immune response, and the oversecretion may lead to cytokine storms\ not all cytokine receptors are tyrosine kinase-associated receptors Non-receptor Tyrosine Kinases (nRTKs) ------------------------------------- these kinases lack extracellular and transmembrane domains; mostly localized in the cytoplasm;\ some are anchored to the cell membrane\ have various domains: tyrosine kinase domain, SH2, SH3, DNA-binding domains; specific domains target the enzymes\ to the cytoplasmic part of cytokine receptors JAKs: Cytoplasmic Protein Tyrosine Kinases ------------------------------------------ the proximity of JAKs associated with the ligand-bound receptors allows for JAKs' cross-phosphorylation and activation\ active JAKs phosphorylate tyrosines on the receptors creating phosphotyrosine docking sites for STATs and other proteins\ with SH2 domains\ active JAKs phosphorylate and activate the latent gene regulatory proteins STATs\ upon activation, STATs dimerize and migrate to the nucleus to activate gene transcription\ through their SH2 domains, the STATs also dock on activated RTKs Focal Adhesion Kinases (FAK): Cytoplasmic Protein Tyrosine Kinases ------------------------------------------------------------------ at focal adhesions, FAK binds the cytosolic tails of integrins through cytoskeletal proteins\ clustered FAK molecules cross-phosphorylate to create docking sites for SRC\ SRC and FAK phosphorylate each other and other proteins SRC Kinases: Cytoplasmic Protein Tyrosine Kinases ------------------------------------------------- SRC is activated through the binding of its SH2 and/or SH3 domains\ N-terminal myristoyl group, SH3, SH2, and tyrosine kinase domains\ activated by several types of receptors Protein Tyrosine Phosphatases (PTPs) ------------------------------------ cytoplasmic or transmembrane\ ensure that tyrosine phosphorylations are short-lived\ some cytoplasmic tyrosine phosphatases have SH2 domains\ transmembrane PTPs are referred to as receptor-like tyrosine phosphatases, and some act as cell-adhesion proteins\ to mediate homophilic cell-to-cell binding\ transmembrane PTPs may also serve as signaling ligands that activate receptors on a neighboring cell Receptor Serine/Threonine Kinases --------------------------------- ligands: transforming growth factor-β (TGF-β) proteins, secreted, dimeric\ the receptors have serine/threonine kinase domains\ the ligand binds/activates a type II receptor homodimer, which activates a type I receptor homodimer to form a tetramer\ type I receptor binds and phosphorylates Smad latent gene regulatory proteins\ phosphorylated Smads dissociate from the receptors and bind to Smad 4 to move to the nucleus Receptor Guanylyl Cyclases -------------------------- mostly single-pass transmembrane proteins with an extracellular binding site for a signal molecule,\ and an intracellular guanylyl cyclase catalytic domain\ ligand binding activates the cyclase domain to produce cyclic GMP\ cGMP activates a cyclic GMP-dependent protein kinase (PKG) that phosphorylates proteins on serine and threonine\ ligands: natriuretic peptides (NPs) and nitric oxide (NO) Nitric Oxide (NO) Gas Signaling ------------------------------- acetylcholine released by autonomic nerves in blood vessel walls induces endothelial cells to release NO,\ which signals the underlying smooth muscle cells to relax; NO is also produced by macrophages and neutrophils\ to kill invading microorganisms\ nitroglycerine is converted to NO, relaxes blood vessels, reduces the heart workload, and reduces the oxygen requirement\ NO is made by the deamination of arginine, catalyzed by NO synthase; NO diffuses out of the producing cell into neighboring cells;\ NO has a short half-life (5--10 seconds)\ NO binds to guanylyl cyclase to stimulate the production of cyclic GMP Positive and Negative Feedback in Signaling ------------------------------------------- What type of feedback would take place, if MEK activates a RAS-specific GEF or a RAS-specific GAP?\ RTK → RAS → RAF → MEK → ERK → gene transcription Putting It Together ------------------- there are five classes of enzyme-linked receptors\ transmembrane tyrosine phosphatases may function as receptors, however, most ligands are unknown\ tyrosine kinase-associated receptors depend on cytoplasmic tyrosine kinases; examples: Src kinases (these can also associate with\ focal adhesion kinase FAK), and Jak kinases, that phosphorylate STATs (dimerized STATs migrate to the nucleus to activate\ gene transcription)\ receptor serine/threonine kinases, activated by TGF-β proteins activate Smads, which oligomerize, migrate to the nucleus,\ and activate gene transcription\ nitric oxide diffuses across the plasma membrane to activate an intracellular enzyme such as cytosolic guanylyl cyclase\ that produces cyclic GMP\ transduction signaling forms "feedback loops", through which downstream players affect upstream players and result\ in suppression or further activation of the signaling