مسیر پیام رسانی سلولی TGF-B

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TGF Beta Signaling Pathway 

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INTRODUCTION Cells communicate with : * membrane-associated proteins + Secreted molecules Why cell needs to contact ? * Proliferation * Differentiation * Metabolism * Behaviour 

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IMPORTANCE Of TGF-Beta Signaling Pathway Among the secreted growth factors and cytokines, the transforming growth factor-b (TGF-b) family receives a lot of attention because of its many functions at the cellular level and in development and its roles in many diseases including cancer. 

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Function of TGF Beta Pathway in Normal Cells - Pattern formation during embryonic development - Cell growth and proliferation - Cellular differentiation - Extracellular matrix production - Angiogenesis - Tissue repair - Immune regulation - Apoptosis 

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PROPERTIES - Secreted ~ function as homodimers or heterodimers - stimulate cell proliferation - strongly inhibits the proliferation of various cell types - promote or protect against cell death - promote extracellularmatrix (ECM) protein expression - cell motility and invasion - control cell metabolism 

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~ The mouse and human genomes have 33 functional genes encoding TGF-b family polypeptides (2). Each of these consists of a signal peptide, required for secretion, a long propolypeptide, and themature polypeptide that, as a dimer, binds and activates the receptors. ~ Besides three TGF-b and five inhibin (activin) polypeptides, the TGF-b family sequences comprisemany that are named BMPs or “growth and differentiation factors” (GDFs) Ref: M. Morikawa, R. Dorynck, K. Miyazono, TGF-b and the TGF-b family: Contextdependent roles in cell and tissue physiology. Cold Spring Harb. Perspect. Biol. 8,4021873 (2016), 

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Ligand processing and A Signal peptide Prodomain Mature peptide B fe ‏مهد‎ ‎Pre-propeptide N- 6 ites ۱ ‏تهمسموى سر‎ Propeptide Be ‏سس‎ Extracellular matrix ¥ 1 3 Homodimer Heterodimer Complex with GARP proposes c Release of ligand ‏ا ا‎ = نوات ۷ ‎LB 6 ae‏ سس واه متخ Plasma membrane Extracellular TGF-6 family receptors matrix 

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Ligand processing and presentation = (A) TGF+b family proteins are synthesized as precursor molecules consisting of a signal peptide, a prodomain (termed latency-associated polypeptide, for TGF-b), and the mature polypeptide. After signal peptide removal, the precursor is further processed by proteolytic cleavage at basic residues, thus separating the prodomain from the mature polypeptide, which remain noncovalently associated. Concomitant, disulfide-linked dimerization of the mature polypeptides then forms mature homodimeric and heterodimeric complexes, as shown. = (B) Latent TGF-b complex can associate through disulfide bonding with latent TGF-b binding protein (LTBP) into a large latent complex (LLC) that, in turn, associates with the ECM (top), or with the plasma membrane-associated glycoprotein- ‘A repetitions predominant (GARP;bottom). (C) Cytoneme-associated activation of TGF-b family signaling is depicted. Long cytonemes extend from the cell body and present TGF-b family receptors to ligand complexes. Binding of ligand to the receptors results in activation of the type I receptors (medium to dark gray) by the type II receptors (light gray). 

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- Four structurally related, dimeric secreted proteins, named glialderived neurotrophic factor (GDNF), neurturin, artemin, and persephin, share key structural similarities with themature TGF-b family ligands but are, based on sequence similarities, more distant from the TGF-b family . 

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Mechanism Ligand Binding - The TGF Beta superfamily of ligands include: Bone morphogenetic proteins (BMPs), Growth and differentiation factors (GDFs), Anti- mullerian hormone (AMH), Activin, Nodal and TGF’s - Signaling begins with the binding of a TGF beta superfamily ligand to a TGF beta type II receptor. - The type II receptor is a serine/threonine receptor kinase, which catalyses the phosphorylation of the Type I receptor. Each class of ligand binds to a specific type II receptor.In mammals there are seven known type I receptors and five type II receptors 

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- There are three activins: Activin A, Activin B and Activin AB. Activins are involved in embryogenesis and osteogenesis. They also regulate many hormones including pituitary, gonadal and hypothalamic hormones as well as insulin. They are also nerve cell survival factors.The BMPs bind to the Bone morphogenetic protein receptor type-2 (BMPR2). They are involved in a multitude of cellular functions including osteogenesis, cell differentiation, anterior/posterior axis specification, growth, and homeostasis. - The TGF beta family include: TGFB1, TGFB2, TGFB3. Like the BMPS, TGF betas are involved in embryogenesis and cell differentiation, but they are also involved in apoptosis, as well as other functions. 

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- They bind to TGF-beta receptor type-2 (TGFBR2). Nodal binds to activin A receptor, type IIB ACVR2B. It can then either form a receptor complex with activin A receptor, type IB (ACVR1B) or with activin A receptor, type IC (ACVR1C) 

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Receptor recruitment and phosphorylation - The TGF beta ligand binds to a type II receptor dimer, which recruits a type I receptor dimer forming a hetero-tetrameric complex with the ligand[4] . These receptors are serine/threonine kinase receptors. They have a cysteine rich extracellular domain, a transmembrane domain and a cytoplasmic serine/threonine rich domain. The GS domain of the type I receptor consists of a series of about thirty serine-glycine repeats[5] . The binding of a TGF beta family ligand causes the rotation of the receptors so that their cytoplasmic kinase domains are arranged in a catalytically favorable orientation. The Type II receptor phosphorylates serine residues of the Type I receptor, which activates the protein. 

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SMAD phosphorylation There are five receptor regulated SMADs: SMAD1, SMAD2, SMAD3,SMAD5, and SMAD9 (sometimes referred to as SMAD8). TGF beta's,Activins, Nodals and some GDFs are mediated by SMAD2 and 3 BMPs, AMH and a few GDFs are mediated by SMAD1, 5۱/۸۲5 200 ۰ OUTSIDE CELL NUCLEUS 

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CoSMAD binding The phosphorylated RSMAD has a high affinity for a coSMAD (e.g. SMAD4) and forms a complex with one. OUTSIDE CELL 

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OUTSIDE CELL Transcription - The phosphorylated RSMAD/coSMAD complex enters the nucleus where it binds transcription promoters/cofactors and causes the transcription of DNA. | NUCLEUS TRANSCRIPTION