Protein Mechanisms

Back to main image bank

Protein O-GlcNAcylation and its effects on the cardiovascular system

Marsh S A , Chatham J C Cardiovasc Res 2011; 89:487-488 - Click here to view the abstract

(A) The O-linked attachment of the monosaccharide N-acetylglucosamine (GlcNAc) moiety to nuclear and cytosolic proteins is a cell signalling process that is similar to and can interact with phosphorylation; this is referred to as protein O-GlcNAcylation, to contrast it with traditional N- and O-glycosylation within the secretory pathways. In contrast to the hundreds of kinases and phosphatases that add and remove phosphate, attachment of O-GlcNAc to proteins is catalyzed by a single enzyme, O-GlcNAc transferase (OGT), and the removal catalyzed by O-GlcNAcase (OGA). Similar to phosphorylation, O-GlcNAc modification of proteins alters their function, activity, subcellular localization, and stability. Synthesis of O-GlcNAc is regulated by the hexosamine biosynthetic pathway; consequently, O-GlcNAc levels are regulated by substrate availability. In addition, however, O-GlcNAcylation is also upregulated in response to cellular stress and this can occur independent of substrate availability.

(B) Chronic upregulation of O-GlcNAcylation in conditions such as diabetes and hypertension is often associated with adverse effects on the cardiovascular system. However, there is increasing evidence demonstrating that O-GlcNAcylation is an essential mediator of cardiac and vascular function, and that acute activation of pathways increasing O-GlcNAc levels are cardioprotective.

Abbreviations:G, GlcNAc; P, phosphate; OGT, O-GlcNAc transferase; OGA, O-GlcNAcase; CV, cardiovascular; I/R, ischemia/reperfusion; ER, endoplasmic reticulum; Ang II, angiotensin II.

Mitochondrial morphology and cardiovascular disease

Ong S , Hausenloy D J Cardiovasc Res 2010;88:16-29 - Click here to view the abstract

Mitochondrial fission

The process of mitochondrial fission is under the control of the mitochondrial fission proteins Drp1 and Fis1. Drp1 is located mainly in the cytosol and comprises a GTPase, a central region, and a GTPase effector domain (GED) or assembly domain. Fis1 is localized in the outer mitochondrial membrane with most of the protein facing into the cytosol, acting as a docking station for Drp1. On activation, Drp1 translocates to the mitochondria (a process which is regulated by phosphorylation and sumoylation), oligomerizes, and constricts the mitochondrial scission site, a process which requires GTPase, thereby resulting in mitochondrial fission.

Mitochondrial morphology and cardiovascular disease

Ong S , Hausenloy D J Cardiovasc Res 2010;88:16-29 - Click here to view the abstract

Mitochondrial fusion

The process of mitochondrial fusion is under the control of the mitochondrial fusion proteins Mfn1 and 2 and OPA-1. Mitochondrial membrane fusion has been shown to be a distinct two-step process which occurs separately for the inner and outer membrane, but in chronology. Both the outer and inner membranes of the mitochondria must fuse properly in order for the matrix contents to mix properly. (A) The mitochondrial fusion proteins Mfn1 and Mfn2 are located on the outer mitochondrial membrane with a cytosolic GTPase domain and two hydrophobic heptad repeat (HR) regions separated by a transmembrane repeat. The C-terminal HR region (HR2) mediates oligomerization between Mfn molecules on adjacent mitochondria, allowing the membranes to fuse. GTP hydrolysis facilitates the fusion process. (B) The mitochondrial fusion protein OPA1 comprises an N-terminal mitochondrial import sequence (MIS), hydrophobic heptad repeat (HR) segments, coiled-coil domain (C C), a GTPase domain, a central domain, and a GTPase effector domain (GED) at the C-terminus. OPA1 mediates the fusion of the inner mitochondrial membranes.

Vasodilator-stimulated phosphoprotein: crucial for activation of Rac1 in endothelial barrier maintenance

Schlegel N, Waschke J Cardiovasc Res (2010) 87(1): 1-3 first published online March 22, 2010 doi:10.1093/cvr/cvq093 - Click here to view the abstract

VASP stabilizes endothelial barrier functions by regulation of small GTPase Rac1.

It is well established in the meantime that vasodilator-stimulated phosphoprotein (VASP) is required to maintain endothelial barrier properties. Under conditions of acute inflammation and hypoxia, VASP was shown to be down-regulated, leading to increased endothelial permeability. Recent data provide evidence for a completely new mechanism by which VASP stabilizes the endothelial barrier, i.e. by facilitating activation of Rac1 downstream of PKA and PKG. According to this model VASP-dependent endothelial barrier stabilization was shown to act via cAMP- and cGMP-mediated signalling pathways. VASP is associated with actin filaments via zyxin and vinculin while paxillin is linked to endothelial adherens junctions via β-catenin. We found that VASP was required for cAMP-mediated Rac1 activation and barrier enhancement. Serine-157 phosphorylation of VASP via PKA induced translocation of VASP to cell junctions and binding of VASP to ZO-1. In line with this, PKG-mediated serine-239 phosphorylation was also shown to be required for Rac1 activation. Thus, we propose that cAMP- and cGMP-mediated signalling facilitates Rac1 activation close to cell junctions in VASP-dependent manner, which in turn appears to be crucial for endothelial barrier stabilization.

Abbreviations: FAK= focal adhesion kinase; PKA= cAMP-dependent protein kinase A; PKG= cGMP-dependent protein kinase G; EPAC= exchange protein directly activated by cAMP; ZO-1/2/3= zonula occludens protein1/2/3; α, β = α- and β-catenin; ECM= extracellular matrix.

Enigma in cardiac hypertrophy

Lompré AM Cardiovasc Res (2010) 86(3): 349-350 first published online March 23, 2010 doi:10.1093/cvr/cvq094 - Click here to view the abstract

Schematic representation of a hypothetical pathway by which the splice variants of ENH could promote or prevent hypertrophy.

The Enigma proteins (ENH) are cytoplasmic proteins that bind to the cytoskeleton and serve as a platform for binding many proteins such as protein kinases. Four ENH isoforms have been described. ENH1, which contains the LIM motif, is expressed in the embryonic and neonatal heart. In the adult heart it is replaced by ENH3, which does not contain this binding motif (Yamazaki et al. Cardiovasc Res 2010,86:374-382). Based upon previously published data showing that the LIM domain anchors PKC and PKD and taking into account the well-described molecular pathways implicated in the hypertrophic effect of these kinases, it is tempting to propose that the LIM domains of ENH1 act as a new signalling platform that mediates the PKC and PKD hypertrophic pathways.

Abbreviations: ENH1-PDZ, enigma homologue 1 PDZ (PSD-95, DLG, ZO-1) domain; ENH1-Lim, enigma homologue 1 Lim (LIN-11, Isl-1, MEC-3) domains; LTCC, L-type voltage-gated Ca²⁺ channel; PKD1, protein kinase D1; PKC, protein kinase C; Id, inhibitor of differentiation/DNA binding; CaMK, Ca²⁺/calmodulin kinase; 14-3-3, chaperone protein 14-3-3; HDAC4,5,9, histone deacetylase type 4, 5, and 9; MEF2, myocyte enhancing factor 2; P, phosphorylation.

High glucose, nitric oxide, and adenosine: a vicious circle in chronic hyperglycaemia?

Cardiovasc Res (2010) 86(1): 9-11 first published online February 17, 2010 doi:10.1093/cvr/cvq055 - Click here to view the abstract

High glucose, NO, and adenosine: a vicious circle in chronic hyperglycaemia.

HUVEC isolated from gestational diabetic pregnancies show a reduced adenosine transport activity via hENT1. This effect of gestational diabetes leads to extracellular accumulation and a higher bioavailability of this nucleoside to activate the A_2a adenosine receptor subtype. The intracellular signalling cascade triggered by A_2a purinoreceptor activation by adenosine results in an increased l-arginine transport activity via hCATs and increased NO synthesis by eNOS. The intracellular second messengers involved in the effect of adenosine include activation of protein kinase C (PKC) and 42/44 kDa mitogen-activated protein kinases (P42/44^mapk), which then activate (+) l-arginine transport. The up-regulation in the endothelial l-arginine/NO pathway by adenosine is associated with an increase in NO. NO activates hCHOP and C/EBPα transcription factor complex formation, which migrates to the nucleus of the endothelial cells and binds, as a complex, to a consensus sequence located on the promoter region of the SLC29A1 gene (for hENT1).

This phenomenon results in reduced transcriptional activity of the SLC29A1 promoter, leading to reduced levels of the hENT1 mRNA and protein. As a consequence, a decreased hENT1 transport-like activity could result in reducing the removal of the endogenous nucleoside adenosine from the extracellular medium in HUVEC. The reduced adenosine transport via hENT1 detected in HUVEC from gestational diabetes could also result from the inhibition (−) by PKC or P42/44^mapk. Notably, hyperglycaemia (glucose) may be proposed as a regulator of the illustrated vicious circle since it might increase (+) both eNOS and NO levels. hCHOP, a key transcriptional regulator of the SLC29A1 gene, has been demonstrated to be increased (+) by high glucose and diabetes.

Paradigm of intracellular and extracellular MMP-2 in cardiac myocytes

Kandasamy AD et al. Cardiovasc Res (2010) 85(3): 413-423 first published online August 4, 2009 doi:10.1093/cvr/cvp268 - Click here to view the abstract

MMP-2 is present in discrete intracellular compartments within the cardiac myocyte (sarcomere, nuclei, caveolae, and mitochondria) as a 72 kD zymogen. It can be activated in two ways that likely dictate its diverse biological roles. Its secretion and proteolytic removal of its autoinhibitory propeptide domain by MT1-MMP together with TIMP-2 results in a 64 kD form that targets extracellular matrix proteins. Oxidative stress, particularly as ONOO^- in the presence of glutathione, causes the S-glutathiolation of a critical cysteine residue in the propeptide and conformational change and activation of the 72 kD form, allowing access of intracellular substrates (troponin I, α-actinin, myosin light chain-1, and titin are thus far known) to its catalytic zinc centre. MMP-2 is also a phosphoprotein (both 72 and 64 kD forms) and phosphorylation markedly reduces its activity (FASEB J 2007;21:2486). The kinases and phosphatases that regulate its activity in vivo are unknown; however, PKC can phosphorylate MMP-2 in vitro. Thus, MMP-2 can ‘remodel’ both intracellular and extracellular protein substrates. The cleavage of intracellular substrates by MMP-2 is an early response to enhanced oxidative stress that results in acute contractile dysfunction.

Abbreviations: matrix metalloproteinase-2 (MMP-2); tissue inhibitor of metalloproteinase-2 (TIMP-2); membrane-type-1 matrix metalloproteinase (MT1-MMP); glutathione (GSH); peroxynitite (ONOO-); protein kinase A (PKA); protein kinase C (PKC)

A schematic illustration of protein quality control (PQC) in the cell

Su H & Wang X Cardiovasc Res (2010) 85(2): 253-262 first published online August 20, 2009 doi:10.1093/cvr/cvp287 - Click here to view the abstract

PQC is carried out by chaperones, the ubiquitin proteasome system (UPS), and the autophagy-lysosome pathway. Chaperones facilitate the folding of nascent polypeptides and the unfolding/refolding of misfolded proteins, prevent the misfolded proteins from aggregating, and escort terminally misfolded proteins for degradation by the UPS. The UPS degrades misfolded proteins and unneeded native proteins in the cell through two general steps: first, covalent attachment of ubiquitin to a target protein by a cascade of chemical reactions catalysed by the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligase (E3); second, the degradation of the target protein by the proteasome. The autophagy-lysosomal pathway helps remove protein aggregates formed by the misfolded proteins that have escaped from the surveillance of chaperones and the UPS. Protein aggregates or defective organelles are first segregated by an isolated double membrane (phagophore) to form autophagosomes, which later fuse with lysosomes to form autophagolysosomes, where the segregated content is degraded by lysosomal hydrolases. p62/SQSTM1 and NBR1 (neighbour of BRCA1 gene 1) may mediate the activation of autophagy by aggregated ubiquitinated proteins. The legend for symbols used is shown in the box at the lower left.

The ubiquitin-proteasome system

Dantuma NP & Lindsten K Cardiovasc Res (2010) 85(2): 263-271 first published online July 25, 2009 doi:10.1093/cvr/cvp255 - Click here to view the abstract

Free ubiquitin proteins are generated from the processing of ubiquitin precursors or ubiquitin chains by deubiquitylation enzymes (DUBs). An enzymatic cascade involving the E1 (ubiquitin activase), E2 (ubiquitin conjugase), and E3 (ubiquitin ligase) enzymes covalently conjugates ubiquitin chains to lysine residues in target proteins. Proteins deemed for degradation are singled out by E3 enzymes through the presence of a degradation signal (degron). The ubiquitylated substrate is recognized by a large proteolytic complex, the proteasome. The proteasome contains of 19S regulatory particles and the 20S core particle, which contains several proteolytic active subunits. The 19S regulatory particle binds, deubiquitylates, unfolds, and translocates the substrate into the proteolytic chamber of the 20S particle where the protein is degraded into short peptide fragments.

The nonsense-mediated mRNA decay – a mRNA surveillance pathway

Carrier L et al. Cardiovasc Res (2010) 85(2): 330-338 first published online July 17, 2009 doi:10.1093/cvr/cvp247 - Click here to view the abstract

MYBPC3 is one of the most frequently mutated genes in hypertrophic cardiomyopathy (HCM). Most mutations result in a frameshift and a premature termination codon (PTC) and should produce truncated proteins, which were never detected in myocardial tissue of patients. Recent data showed that the nonsense-mediated mRNA decay (NMD) is involved in the degradation of nonsense mRNA in a mouse model of HCM (Vignier, Schlossarek et al., Circ Res 2009). NMD is an evolutionarily conserved pathway existing in all eukaryotes that detects and eliminates PTC-containing transcripts. NMD apparently evolved to protect the organism from the deleterious dominant-negative or gain-of-function effects of resulting truncated proteins.

(A) NMD occurs when a PTC is located more than 50–55 nucleotides (nt) upstream of the last exon–exon junction within the mRNA (green region), whereas mRNAs with PTCs downstream of this boundary (red region) escape NMD. (B) During pre-mRNA splicing, exon junction complexes (EJC) are deposited upstream of every exon–exon junction. In normal transcripts, EJCs are displaced by the ribosome during the pioneer round of translation, and translation stops when the ribosome reaches the normal stop codon. In contrast, in PTC-bearing mRNAs, the ribosome is blocked at the PTC and the EJC downstream of the PTC remains associated with the mRNA. This results in attachment of the SURF complex to the ribosome. Subsequent phosphorylation of UPF1 by SMG-1 drives dissociation of eRF1 and eRF3 and binding of SMG7. Ultimately, the mRNA is degraded by different pathways including decapping or deadenylation.

The role of the protein degradation systems in viral myocarditis leading to dilated cardiomyopathy

Luo H et al. Cardiovasc Res (2010) 85(2): 347-356 first published online July 3, 2009 doi:10.1093/cvr/cvp225 - Click here to view the abstract

Viral myocarditis is an inflammatory disease of the myocardium caused by virus infection. The disease progression occurs in three distinct stages: viral infection, immune response, and cardiac remodelling. Recent evidence suggests that the host proteolytic systems play crucial roles in the regulation of the pathogenesis of viral myocarditis in all three stages. During the viral infection stage, the virus evolves different strategies to utilize the host ubiquitin/proteasome system and the autophagy machinery to facilitate its replication. At the immune response stage, viral infection induces the formation of an immunoproteasome to increase MHC class I antigen presentation. Meanwhile, production of pro-inflammatory cytokines is enhanced, partially through the ubiquitin/proteasome system-mediated NFκB activation. Autophagy may also contribute to immune-mediated pathogenesis by modulating MHC class II antigen presentation. During the cardiac remodelling phase, increased accumulation of abnormal ubiquitin-protein conjugates/aggregates and elevated oxidative stress lead to the eventual impairment of the ubiquitin/proteasome function, subsequently resulting in abnormal regulation of contractile apparatus expression and also triggering apoptosis and autophagic cell death. As a result of myocyte loss and decreased contractile properties, the left ventricle of the heart begins to dilate to compensate for impaired cardiac function.

SAFE PATHWAY: An alternate cardioprotective signalling route

Lacerda L et al. Cardiovasc Res (2009) 84(2): 201-208 first published online August 7, 2009 doi:10.1093/cvr/cvp274 - Click here to view the abstract

Activation of the survivor activating factor enhancement (SAFE) pathway, as represented by the binding of a low concentration of endogenous or exogenous tumour necrosis factor alpha (TNFα) to its TNF receptor 2 (TNFR2) at the onset of reperfusion with the subsequent activation of the transcription factor signal transducer and activator of transcription-3 (STAT-3), initiates a cardioprotective signalling cascade in both ischaemic pre- and postconditioning that is activated independently of the well-known reperfusion injury salvage kinases (RISK) pathway. The delineation of the SAFE pathway further emphasizes the importance of RISK-independent pathways in cardioprotection, which may have potential therapeutic application in the mitigation of ischaemic-reperfusion injury.

Abbreviations: RISK: Reperfusion Injury Salvage Kinases; SAFE: Survivor Activating Factor Enhancement; S1P: sphingosine-1-phosphate; TNFα: tumour necrosis factor alpha; GPCR: green protein coupled receptors; S1P R1/R3: sphingosine-1-phosphate receptors 1 or 3; TNFR2: tumour necrosis factor alpha receptor 2; MEK: mitogen-activated protein kinase; PI3K: phosphoinositide 3- kinase; Erk1/2: extracellular regulated kinases 1/2; Akt: protein kinase B; GSK-3β: glycogen synthase kinase-3 beta; JAK: janus kinase; STAT-3: signal transducer and activator of transcription-3; mPTP: mitochondrial permeability transition pore; P: phosphorylation

mPTP regulation by ANT (adenine nucleotide translocator), CyP-D (cyclophilin D), and P_i

Zorov DB et al. Cardiovasc Res (2009) 83(2): 213-225 first published online May 15, 2009 doi:10.1093/cvr/cvp151 - Click here to view the abstract

The core structure of the mPTP remains unresolved. Known mPTP regulatory elements are depicted on the left side of the figure, whereas the right side indicates symbolically the threshold for mPTP-induction by oxidant stress. The middle row (horizontally) depicts the basal state of ANT and CyP-D as they relate to the basal threshold for mPTP induction by oxidant stress. The top row reflects factors that facilitate mPTP induction: atractyloside, Ca²⁺, and indirect effects of P_i. The bottom row includes factors that are known to inhibit mPTP induction: genetic deletion of ANT (ANT is dispensable for mPTP formation per se; inhibition of CyP-D by CsA remains protective), ADP, or bongkrekic acid (requirement/role of CyP-D under these conditions is unknown), CsA and genetic deletion of CyP-D in the presence of P_i (atractyloside, CsA and Ca²⁺ are no longer effective when compared with WT). Note the opposing mechanisms of P_i in mPTP induction: (i) P_i as a direct mPTP desensitizer (bottom row) is opposed by CyP-D binding (top row), whereas (ii) P_i may also act as an indirect mPTP sensitizer (through regulation of Mg²⁺ and/or polyphosphate levels; top row). Note that Ca²⁺ is not a major factor in mPTP induction in intact cardiomyocytes and neurons.

Abbreviations:
mPTP mitochondrial permeability transition pore
ANT adenine nucleotide translocator
BKA bongkrekic acid
CyP-D cyclophilin D
P_i inorganic phosphate
CsA cyclosporin A
ADP adenosine diphosphate
Ppif gene encoding CyP-D in mouse
WT wild-type

Protein kinase activation in cardioprotection

Boengler K et al. Cardiovasc Res (2009) 83(2): 247-261 first published online January 28, 2009 doi:10.1093/cvr/cvp033 - Click here to view the abstract

There are three major signalling cascades of protein kinase activation in cardioprotection: (A) the GPCR/NPR-AKT-eNOS-PKG pathway, (B) the reperfusion-injury salvage kinase (RISK) pathway, and (C) the survival activating factor enhancement (SAFE) pathway, which centrally involves gp130-JAK-STAT signalling. In each system, there are molecules that are decreased in expression and/or activity with advancing age (marked in yellow) and possibly contribute to the loss of cardioprotection with aging. Such loss of cardioprotection with aging is one major problem in the translation of experimental data from (usually young and healthy) animals to the clinical situation in elderly humans.

Abbreviations: AMPK, AMP-activated kinase; ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; CB-R, cannabinoid receptor; Cx43, connexin 43; eNOS, endothelial NO synthase; ERK, extracellular regulated kinase; FGF-2, fibroblast growth factor 2; gp130, glycoprotein 130; GPCR, G-protein-coupled receptor; GSK3β, glycogen synthase kinase 3 β; H11K, H11 kinase; IGF, insulin-like growth factor 1; IL-6, interleukin 6; iNOS, inducible NO synthase; JAK, janus kinase; KATP, ATP-dependent potassium channel, MnSOD, manganese superoxide dismutase; MPTP, mitochondrial permeability transition pore; NO, nitric oxide; NPR, natriuretic peptide receptor; p38, p38 mitogen activated protein kinase; P70S6K, p70 ribsosomal S6 protein kinase; pGC, particulate guanylyl cyclase; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PKG, protein kinase G; ROS, reactive oxygen species; sGC, soluble guanylyl cyclase; SIRT1, sirtuin 1; STAT3, signal transducer and activator of transcription 3; TNF-R, tumour necrosis factor receptor; UCN, urocortins.

Cardioprotective growth factors

Cardiovasc Res (2009) 83(2): 179-194 first published online February 13, 2009 doi:10.1093/cvr/cvp062 - Click here to view the abstract

This schematic provides a simplified overview of the intracellular transduction pathways underlying cardioprotection elicited by the growth factors: transforming growth factor-β1 (TGF-β1), cardiotrophin-1 (CT-1), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), insulin, insulin-like growth factor (IGF), and urocortin. Ligand binding to their respective cell-surface receptors on the cardiomyocyte activates intracellular signalling kinase cascades including Raf-Ras-Mek1/2-Erk1/2 and PI3K-Akt of the reperfusion injury salvage kinase (RISK) pathway, the JAK-STAT pathway, and various anti-apoptotic mechanisms (including the phosphorylation and inhibition of Bax and BAD as well as the inhibition of cytochrome C release).

Many of the acute cardioprotective mechanisms manifested at the time of reperfusion converge on the mitochondria and include the inhibition of the mitochondrial permeability transition pore (mPTP), which can be achieved through several different mechanisms including the phosphorylation and inhibition of GSK3β; the opening of the ATP-sensitive mitochondrial potassium (Mito K_ATPM) channel by the eNOS-NO-PKG-PKC-ε cascade which produces mitochondrial ROS, which inhibits mitochondrial permeability transition pore opening; and the intracellular calcium modulation due to augmented SERCA uptake of calcium into the sarcoplasmic reticulum. More long-term cardioprotection may be achieved through the genetic transcription of various cardioprotective mediators such as iNOS, NF_κB, MMP-1, phospholipase-1, and so on (not shown on diagram, see text for details).

Myocardial protection by nitrite

Cardiovasc Res (2009) 83 (2): 195-203. doi: 10.1093/cvr/cvp079 - Click here to view the abstract

Nitrite homeostasis is determined by nitric oxide (NO) generation from NO synthases and dietary consumption of nitrate. Nitrate enters the stomach and then circulates in the blood and is converted into nitrite via salivary bacteria containing nitrate reductase. Nitrite derived from the diet and NOS activity rapidly accumulates in the plasma and is transported into tissues such as the heart. Nitrite is then stored in the myocardium and is metabolized into NO during hypoxia or ischaemia.

VEGF receptor switching in heart development and disease

Cardiovasc Res (2009) 84(1): 4-6 first published online August 4, 2009 doi:10.1093/cvr/cvp270 - Click here to view the abstract

A schematic representation of the cardiomyocyte VEGF signalling pathway. Flt-1 and KDR are the two major VEGF receptors. In cardiomyocytes, VEGF drives cardiac hypertrophy or its regression, depending on the prevalent binding to KDR or Flt-1, respectively. Copper (Cu) supplementation determines a switch in the VEGF signalling pathway, increasing the ratio of Flt-1 to KDR. By this mechanism, copper induces regression of cardiomyocyte hypertrophy.

Abbreviations: VEGF, vascular endothelial growth factor; Flt-1, FMS-like tyrosine kinase-1; KDR, kinase insert domain receptor; PKG-1, cGMP-dependent protein kinase-1; Cu, copper; DAG, diacylglycerol; IP3, inositol trisphosphate; Sos, Son of Sevenless; Shc, Src-homology collagen protein; Grb-2, growth factor receptor-bound protein 2; MEK1/2, mitogen activated protein kinase (MAPK)/extracellular-regulated kinase (ERK) kinase 1/2; PKC, protein kinase C; PLC-γ, phospholipase C-γ; PD98059 (PD) and UO126 are selective ERK1/2 inhibitors.

Back to top of page

• Site Map
• Privacy Policy
• Frequently Asked Questions