Enzymes, proteins, riboproteins and signaling pathways.

serine/threonine kinases

Several serine/threonine kinases function in signal transduction pathways. These are receptors for the TGF-β superfamily of ligands, and have intrinsic serine/threonine kinase (phosporylating) activity.

Serine/threonine kinases that are activated by mitogens and play a role in apoptosis belong to the mitogen-activated protein kinase (MAPK) family whose members participate in the MAPK signaling cascade:
mitogen → MAPKK kinase (MAPKKK) → MAPK kinase (MAPKK) → MAP kinase (MAPK) → signaling

Specifically, these are the mitogen activated protein kinases (MAP kinases, MAPKs): p42/44 ERK, p38 MAPK and c-Jun N-terminal kinase (JNK), cyclic AMP-dependent protein kinase (PKA), protein kinase B (PKB), or Akt and protein kinase C (PKC).

cAMP-dependent protein kinase cyclin-dependent kinasesAkt ♦ ERKs ~ ERKs ♦ ♦ MAPKsMEKsmitogen activated protein kinases ♦ ♦ MPFM-phase promoting factormTOR ♦ ♦ PDK1PTENPIKKPI3KPKAPKBPKCsprotein kinasesRaf

The signaling pathways utilized by the TGF-β, activin, and BMP receptors are different than those for receptor tyrosine kinases (RTKs) or receptors associated with intracellular protein tyrosine kinases (PTKs). Ligands first bind to the type II receptors, and this binding leads to interaction with the type I receptors. Once the complex between ligand and the two receptor subtypes has formed, the type II receptor phosphorylates the type I receptor, which leads to initiation of the signaling cascade. A predominant role of TGF-beta is the regulation of progression through the cell cycle. The proto-oncogene, c-Myc ("mick"), which directly affects the expression of genes harboring Myc-binding elements, is a nuclear protein involved in the responses of cells to TGF-β .

a) cAMP-dependent protein kinase (protein kinase A, PKA - enzymes whose catalytic (protein phosporylating) activity is modulated by cAMP levels. PKA is highly conserved with RTKs.

b) protein kinase Cs (PKCs) - enzymes that exhibit specific patterns of tissue expression and activation by lipid and calcium. PKCs are maximally active in the presence of calcium ion and diacylglycerol. PKC activity is mediated by receptors that are coupled to activation of phospholipase C-gamma (PLC-gamma), which contains SH2 domains that enable it to interact with tyrosine phosphorylated RTKs. Phospholipases D and A2 (PLD, PLA2) sustain the activation of PKC through their hydrolysis of membrane phosphatidylcholine (PC). Activation of PLC-gamma results in hydrolysis of membrane phosphatidylinositol bisphosphate (PIP2), which leads to an elevation of intracellular diacylglycerol (DAG) and inositol trisphosphate (IP3), which interacts with intracellular membrane receptors to effect release of stored calcium ions. PKCs are involved in signal transduction pathways initiated by specific hormones, growth factors and neurotransmitters.

c) mitogen activated protein kinases (MAP kinases), which act as switch kinases that transmits information of increased intracellular tyrosine phosphorylation to that of serine/threonine phosphorylation. MAP kinases are also called ERKs for extracellular-signal regulated kinases, microtubule associated protein-2 kinase (MAP-2 kinase), myelin basic protein kinase (MBP kinase), ribosomal S6 protein kinase (RSK-kinase) and EGF receptor threonine kinase (ERT kinase). Maximal MAP kinase activity requires phosphorylation of both tyrosine and threonine residues.

Some signaling molecules act as adhesion receptors, which cluster in focal adhesions upon ligand binding. Focal adhesions are rich in tyrosine phosphorylated proteins, coupling cell adhesion to signal transduction pathways in the cell. Various adhesion receptors, such as integrin, are closely linked to protein kinases and phosphatases.

A variety of integrins, which are transmembrane heterodimeric adhesion receptors are known to support adhesion-dependent growth factor-activation of MAP kinase.

The catalytic domains of kinases are highly conserved, but sequence variation in the kinome (subset of genes that encode kinases) provides for recognition of distinct substrates.

Tables  Cell signaling  Receptor Tyrosine Kinases(RTK) :

phosphotransfer-mediated signaling pathwaysProtein Kinase Signaling Networksreceptor tyrosine kinases •  Receptor Tyrosine Kinases (RTKs)signaling gradientstwo-component systems • animation MAPK signal transduction : animation G-protein :

Signaling pathways:
Pathway ABC transporters : Pathway Phosphotransferase system (PTS) : Pathway Two-component system : Pathway MAPK signaling pathway : Pathway Wnt signaling pathway : Pathway Notch signaling pathway : Pathway Hedgehog signaling pathway : Pathway TGF-beta signaling pathway : Pathway VEGF signaling pathway : Pathway Jak-STAT signaling pathway : Pathway Calcium signaling pathway : Pathway Phosphatidylinositol signaling system : Pathway mTOR signaling pathway : Pathway Neuroactive ligand-receptor interaction : Pathway Cytokine-cytokine receptor interaction : Pathway ECM-receptor interaction : Pathway Cell adhesion molecules (CAMs) :

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