Chemistry of Life

Molecular genetics, biochemistry

serine/threonine kinases

Several serine/threonine kinases function in signal transduction pathways. These are associated with receptors of the TGF-β superfamily that employ intrinsic serine/threonine kinase (phosporylating) activity to signal through the Smad family of proteins.

The signaling pathways utilized by the TGF-β, activin, and BMP receptors are different than those for receptor tyrosine kinases (RTKs) or receptor proteins associated with intracellular protein tyrosine kinases (PTKs). In TGF-β signaling, transforming growth factor β first binds 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. The activated type I receptor then phosphorylates and activate the Smad2 protein, which, complexed with Smad4, is translocated to the nucleus. The activated Smad complex recruits other transcription factors, and together they activate the expression of target genes that mediate the biological effects of TGF-β. A predominant role of TGF-β is the regulation of progression through the cell cycle. Some of the activated target genes suppress tumorigenesis, while others stimulate tumorigenesis. The proto-oncogene, c-Myc ("mick") is a nuclear protein involved in the responses of cells to TGF-β, which directly affects the expression of genes harboring Myc-binding elements.

cAMP-dependent protein kinase ¤ carcinogenesis : ERKs : focal adhesion : mitogen activated protein kinases : MAPK signaling cascade : MAPK responses : PKA · protein kinase A : protein kinase Cs : signaling and adhesion : TGF-β ¤ mitogens ¤

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 are maximally active in the presence of second messengers 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 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, when activated by mitogens, act as switch kinases that transmit information of increased intracellular tyrosine phosphorylation to that of serine/threonine phosphorylation. Maximal MAP kinase activity requires phosphorylation of both tyrosine and threonine residues.

The MAPK signaling cascade is:
mitogen → MAPKK kinase (MAPKKK) → MAPK kinase (MAPKK) → MAP kinase (MAPK) → signaling

All eukaryotic cells possess multiple MAPK pathways [K], which coordinately regulate diverse cellular activities running the gamut from gene expression, mitosis, and metabolic regulation to motility, survival and apoptosis, and cellular differentiation. To date, five distinct groups of MAPKs have been characterized in mammals: extracellular signal-regulated kinases (ERKs) 1 and 2 (ERK1/2), c-Jun amino-terminal kinases 1, 2, and 3 (JNKs, or SAPK, stress-activated protein kinases), p38 isoforms α, β, γ, and δ, ERKs 3 and 4, and ERK5 (reviewed in references 25 and 103).[s-fft]

Other MAP kinases include: 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). MAP kinases include extracellular-signal regulated kinases (ERKs), with activators that include mitogens: Ras [fft], polypeptide growth factors PDGF, CSF-1, IGF-1, EGF, insulin, and PMA.

MAPK responses :
a. growth factors, mitogens, Ras → extracellular-signal regulated kinases (ERKs) - TrkA/B, EGFR, FGFR, PDHFR → cellular proliferation and cellular differentiation
b. cellular stress stimuli such as cytokines, physical shock → stress-activated protein kinases (SAPKs, JNKs) → cellular differentiation, inflammation, or apoptosis
c. growth factors and cellular stress stimuli → ERK-5 → cellular proliferation

Signaling and Adhesion: 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)  Cell Adhesion Molecules  Immune Cytokines  Second Messengers 

¤ carcinogenesisphosphotransfer-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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