Signal Transduction

Signal transduction is a process in which extracellular signals elicit changes in cell state and activity. Transmembrane receptors sense changes in the cellular environment by binding ligands, such as hormones and growth factors, or reacting to other types of stimuli, such as light. Stimulation of transmembrane receptors leads to their conformational change which propagates the signal to the intracellular environment by activating downstream signaling cascades. Depending on the cellular context, this may impact cellular proliferation, differentiation, and survival. On the organism level, signal transduction regulates overall growth and behavior.<br>Receptor tyrosine kinases (RTKs) transmit extracellular signals by phosphorylating their protein partners on conserved tyrosine residues. Some of the best studied RTKs are EGFR (reviewed in Avraham and Yarden, 2011), FGFR (reviewed in Eswarakumar et al, 2005), insulin receptor (reviewed in Saltiel and Kahn, 2001), NGF (reviewed in Reichardt, 2006), PDGF (reviewed in Andrae et al, 2008) and VEGF (reviewed in Xie et al, 2004). RTKs frequently activate downstream signaling through RAF/MAP kinases (reviewed in McKay and Morrison, 2007 and Wellbrock et al 2004), AKT (reviewed in Manning and Cantley, 2007) and PLC- gamma (reviewed in Patterson et al, 2005), which ultimately results in changes in gene expression and cellular metabolism. <br>Receptor serine/threonine kinases of the TGF-beta family, such as TGF-beta receptors (reviewed in Kang et al. 2009) and BMP receptors (reviewed in Miyazono et al. 2009), transmit extracellular signals by phosphorylating regulatory SMAD proteins on conserved serine and threonine residues. This leads to formation of complexes of regulatory SMADs and SMAD4, which translocate to the nucleus where they act as transcription factors. <br>WNT receptors transmit their signal through beta-catenin. In the absence of ligand, beta-catenin is constitutively degraded in a ubiquitin-dependent manner. WNT receptor stimulation releases beta-catenin from the destruction complex, allowing it to translocate to the nucleus where it acts as a transcriptional regulator (reviewed in MacDonald et al, 2009 and Angers and Moon, 2009). WNT receptors were originally classified as G-protein coupled receptors (GPCRs). Although they are structurally related, GPCRs primarily transmit their signals through G-proteins, which are trimers of alpha, beta and gamma subunits. When a GPCR is activated, it acts as a guanine nucleotide exchange factor, catalyzing GDP to GTP exchange on the G-alpha subunit of the G protein and its dissociation from the gamma-beta heterodimer. The G-alpha subunit regulates the activity of adenylate cyclase, while the gamma-beta heterodimer can activate AKT and PLC signaling (reviewed in Rosenbaum et al. 2009, Oldham and Hamm 2008, Ritter and Hall 2009). <br>NOTCH receptors are activated by transmembrane ligands expressed on neighboring cells, which results in cleavage of NOTCH receptor and release of its intracellular domain. NOTCH intracellular domain translocates to the nucleus where it acts as a transcription factor (reviewed in Kopan and Ilagan, 2009). <br>Integrins are activated by extracellular matrix components, such as fibronectin and collagen, leading to conformational change and clustering of integrins on the cell surface. This results in activation of integrin-linked kinase and other cytosolic kinases and, in co-operation with RTK signaling, regulates survival, proliferation and cell shape and adhesion (reviewed in Hehlgans et al, 2007) . <br>Besides inducing changes in gene expression and cellular metabolism, extracellular signals that trigger the activation of Rho GTP-ases can trigger changes in the organization of cytoskeleton, thereby regulating cell polarity and cell-cell junctions (reviewed in Citi et al, 2011).

信号转导是一种过程，其中细胞外信号引发细胞状态和活动的改变。跨膜受体通过结合配体，如激素和生长因子，或对其他类型的刺激，如光，作出反应，从而感知细胞环境的改变。跨膜受体的刺激导致其构象变化，通过激活下游信号级联反应，将信号传递至细胞内环境。根据细胞环境的不同，这可能影响细胞的增殖、分化和存活。在生物体层面，信号转导调节整体生长和行为。<br>受体酪氨酸激酶（RTK）通过在保守酪氨酸残基上磷酸化其蛋白质伙伴来传递细胞外信号。其中一些研究最为深入的RTK包括EGFR（参见Avraham和Yarden，2011年的综述）、FGFR（参见Eswarakumar等，2005年的综述）、胰岛素受体（参见Saltiel和Kahn，2001年的综述）、NGF（参见Reichardt，2006年的综述）、PDGF（参见Andrae等，2008年的综述）和VEGF（参见Xie等，2004年的综述）。RTK通常通过RAF/MAP激酶（参见McKay和Morrison，2007年及Wellbrock等，2004年的综述）、AKT（参见Manning和Cantley，2007年的综述）和PLC-γ（参见Patterson等，2005年的综述）激活下游信号，最终导致基因表达和细胞代谢的改变。<br>TGF-β家族的受体丝氨酸/苏氨酸激酶，如TGF-β受体（参见Kang等，2009年的综述）和BMP受体（参见Miyazono等，2009年的综述），通过在保守丝氨酸和苏氨酸残基上磷酸化调节性SMAD蛋白来传递细胞外信号。这导致调节性SMADs和SMAD4形成复合物，这些复合物转移到细胞核中，在那里它们作为转录因子发挥作用。<br>WNT受体通过β-连环蛋白传递其信号。在没有配体的情况下，β-连环蛋白以泛素依赖性方式恒定降解。WNT受体的刺激释放β-连环蛋白从破坏复合物中，使其能够转移到细胞核中，在那里它作为转录调控因子发挥作用（参见MacDonald等，2009年及Angers和Moon，2009年的综述）。WNT受体最初被归类为G蛋白偶联受体（GPCR）。尽管它们在结构上相关，GPCR主要通过G蛋白传递其信号，G蛋白是α、β和γ亚基的三聚体。当GPCR被激活时，它作为鸟苷酸交换因子，催化G蛋白α亚基上的GDP到GTP交换，并使其从γ-β异二聚体中解离。G蛋白α亚基调节腺苷酸环化酶的活性，而γ-β异二聚体可以激活AKT和PLC信号（参见Rosenbaum等，2009年、Oldham和Hamm，2008年、Ritter和Hall，2009年的综述）。<br>NOTCH受体由相邻细胞表达的跨膜配体激活，导致NOTCH受体裂解及其细胞内域的释放。NOTCH细胞内域转移到细胞核中，在那里它作为转录因子发挥作用（参见Kopan和Ilagan，2009年的综述）。<br>整合素由细胞外基质成分，如纤连蛋白和胶原蛋白，激活，导致整合素在细胞表面的构象变化和聚集。这导致整合素连接激酶和其他细胞质激酶的激活，并与RTK信号协同调节细胞的存活、增殖、形态和粘附（参见Hehlgans等，2007年的综述）。<br>除了诱导基因表达和细胞代谢的改变外，触发Rho GTP-ases激活的细胞外信号还能够触发细胞骨架组织的改变，从而调节细胞极性和细胞间连接（参见Citi等，2011年的综述）。