信号通路和肿瘤.PPT

Receptor Serine/Threonine Kinases (RSTKs) Typical example: Receptors for the TGF-? superfamily of ligands The TGF-? superfamily include 30 multifunctional proteins, e.g., activins, inhibins and the bone morphogenetic proteins (BMPs). 17 RSTKs isolated are in 2 subfamilies: type I and type II receptors. Nuclear proteins responding to TGF-? activation include c-Myc and Smad Ligands bind to the type II receptors Complexed with type I receptors Type II R phosphorylates type I receptor Initiation of signaling cascade Non-Receptor Serine/Threonine Kinases 1) cAMP-dependent protein kinase (PKA) 2) Protein kinase C (PKC) 3) Mitogen activated protein kinases (MAPK or ERK) (requiring phosphorylation of both tyrosine and threonine) G-Protein Coupled Receptors 1. 1000 GPCRs, most of which are orphan receptors) 2. Three different classes of GPCR: GPCRs that modulate adenylate cyclase activity and produce cAMP GPCRs that activate PLC-g leading to hydrolysis of polyphosphoinositides: angiotensin, bradykinin and vasopressin receptors. Photoreceptor Intracellular Hormone Receptors 1. Residing within the cytoplasm. 2. The steroid/thyroid hormone receptor superfamily (e.g. glucocorticoid, vitamin D, retinoic acid and thyroid hormone receptors): bind steroid/thyroid hormone, translocate to nuclear and bind specific DNA sequences hormone response elements (HREs). ?* Phosphatases in Signal Transduction 1. Transmembrane PTPs: e.g., CD45. 2. Intracellular PTPs. 胞外信号分子(可溶性分子、细胞表面分子、组织基质分子) 靶细胞跨膜分子(狭义受体如EGFR或广义受体如Integrin) 靶细胞受体（胞内段）化学变化（如磷酸化、二聚体形成） 靶细胞内信号转导分子化学变化与激活 （如磷酸化、去磷酸化、聚体形成） 激活的信号转导分子进入胞核 进入胞核的转导分子作用于基因转录调控区?基因表达改变 信号转导研究中的重大理论问题及热点领域 信号转导通路的调控 磷酸化—去磷酸化调控 信号转导分子消长的调控（分子半衰期） 不同通路之间的效应调控 胞内内源性抑制物的调控功能 Cross-Talk 信号转导效应的特异性When and Where?????? Cooperation with other signaling pathways? Pre-existing transcription co-factors differentially expressed and activated in different cell types? Pre-existing co-activators of target proteins? Subcellular localization