Pathway: Regulation of PTEN stability and activity
Reactions in pathway: Regulation of PTEN stability and activity :
Regulation of PTEN stability and activity
PTEN protein stability is regulated by ubiquitin ligases, such as NEDD4, WWP2, STUB1 (CHIP), XIAP, MKRN1 and RNF146, which polyubiquitinate PTEN in response to different stimuli and thus target it for proteasome-mediated degradation (Wang et al. 2007, Van Themsche et al. 2009, Maddika et al. 2011, Ahmed et al. 2012, Lee et al. 2015, Li et al. 2015). Several ubiquitin proteases, such as USP13 and OTUD3, can remove polyubiquitin chains from PTEN and rescue it from degradation (Zhang et al. 2013, Yuan et al. 2015). TRIM27 (RFP) is an E3 ubiquitin ligase that polyubiquitinates PTEN on multiple lysines in the C2 domain of PTEN using K27 linkage between ubiquitin molecules. TRIM27 mediated ubiquitination inhibits PTEN lipid phosphatase activity, but does not affect PTEN protein localization or stability (Lee et al. 2013).
PTEN phosphorylation by the tyrosine kinase FRK (RAK) inhibits NEDD4 mediated polyubiquitination and subsequent degradation of PTEN, thus increasing PTEN half life. FRK mediated phosphorylation also increases PTEN enzymatic activity (Yim et al. 2009). Casein kinase 2 (CK2) mediated phosphorylation of the C-terminus of PTEN on multiple serine and threonine residues increases PTEN protein stability (Torres and Pulido 2001) but results in ~30% reduction in PTEN lipid phosphatase activity (Miller et al. 2002).
PREX2, a RAC1 guanine nucleotide exchange factor (GEF) can binds to PTEN and inhibit its catalytic activity (Fine et al. 2009).
PTEN phosphorylation by the tyrosine kinase FRK (RAK) inhibits NEDD4 mediated polyubiquitination and subsequent degradation of PTEN, thus increasing PTEN half life. FRK mediated phosphorylation also increases PTEN enzymatic activity (Yim et al. 2009). Casein kinase 2 (CK2) mediated phosphorylation of the C-terminus of PTEN on multiple serine and threonine residues increases PTEN protein stability (Torres and Pulido 2001) but results in ~30% reduction in PTEN lipid phosphatase activity (Miller et al. 2002).
PREX2, a RAC1 guanine nucleotide exchange factor (GEF) can binds to PTEN and inhibit its catalytic activity (Fine et al. 2009).
Second messengers are generated within the cell as a downstream step in signal transduction cascades initiated by the interaction of an external stimulus with a cell surface receptor. Common second messengers include DAG, cAMP, cGMP, IP3, Ca2+ and phosphatidylinositols (reviewed in Kang et al, 2015; Raker et al, 2016; Li and Marshall, 2015; Pinto et al, 2015; Ahmad et al, 2015).
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.
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.
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.
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).
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).
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) .
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).
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.
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.
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).
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).
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) .
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).