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Protein kinases : Role in cell signaling & implication in human
pathologies
Jayanti Tokas1, Rubina Begum1, Shalini Jain2 and Hariom Yadav2
1Department of Biotechnology, JMIT, Radaur
2 NIDDK, National Institute of Health, Bethesda,MD20892, USA
Email: [email protected]
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Protein Kinase
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30% of all proteins may be modified
518 protein kinase genes=human kinome space
20% of all eukaryotic genes(human genome project)
218 genes=human diseases
Approx 30=tumor suppressor
Approx 100 dominant oncogenes
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Kinases Protein phosphorylation cell signalingKinases Protein phosphorylation cell signaling
Reversible protein phosphorylation as a biological regulatory mechanism
Edmond H. Fischer and Edwin G. Krebs (1992 Nobel Prize for Physiology and Medicine).
Post-translational modification in the cell
• Cell growth/proliferation• Differentiation• Viability/survival• Homeostasis• Effector function (e.g. cytotoxicity, cytokine production)• Cell death
‘signal’
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Signal Transduction and Kinase Pathways
Nucleus MAP kinase,• Transcription factors– Bind consensus sequence on
promoter– May form complexes– May itself be transcribed following cellular activation
Adaptor proteins
Effector enzymes
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Classification
On the basis of amino acid :
Tyrosine kinases,
Serine threonine (PKC, Plk,Rho Kinases)
Receptor (EGFR,FGFR,PDGFR)
non receptor (JAK,src,Abl,MAPK)
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Tyrosine kinase
structure
function:
Related pathologies
Serine threonine kinases Related pathology
Check points
Check points
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Structure
Bioblar structure
N and c
N-beta sheets
C-alpha helix
ATP bind-cleft at intetrsection
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How they function:
Mechanisms of Activation of Normal TKs.
survivalDifferentiation Motility Proliferation
May oligomerise
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ControlAutoinhihibitory transmembrane interactions cytoplasmic juxtamembrane region further inhibits the enzyme by interacting with the kinase domain Autophosphorylation---. reorient critical amino acid residues increasing catalytic activityinhibitor proteins and lipidsIF CONTROL LOST
Loss of function
Gain of function
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Mechanisms of TK Dysregulation
oPDGF EGFVEGFFGFKL
oPDGFREGFRHER2c-KITFGFR3
Overexpression of receptor or ligand
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EGFRSuperfamily with 4 receptors
C-ERBB
C-ERBB2
C-ERBB3
C-ERBB4
Cell proliferationInhibition of apoptosisAngiogenesisCell motilitymetastasis
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Carcinogenesis:colorectal cancer, lung cancer(enhanced responsiveness),glioblastoma
multiforme(constitutive active)
Over expressed & mutated
Deletions(exon 2-7:alternative splicing)
or point mutations(Ile654Val)
Dysregulation
Cell proliferation inh of apoptosis angiogenesis metastasis
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Check points
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FLT3
C-KIT
PDGFR
EGFRHER2
Mutation in receptor tyrosine kinase causing constitutive expression
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PDGFR
Tyrosine kinase
fibroblasts,smooth muscles of lung and airways
Mesenchymal cell migration and proliferation
Angiogenesis and blood vessel maintainance
Dysfunction:
Abnormal vasulature irregular diameter leakiness
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• Glioblastoma
• Atherosclerosis
• Pathological conditions:del(4q12) ; t(4;22)
• Adenocarcinoma
• Breast
• Colon
• Prostate
• Stomach
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Cell growth
Differentiation
Chemotaxis
Angiogenesis
Cell survival
SKELETAL SYSTEM
Dysfunction
60 mutations
FGFR2 craniosynostosis syndrom(premature ossification of skull)
Pfeiffer syndrome(additional fingers
FGFR3 achondroplasia(dwarfism)
Gly380Arg Gly375Cys
Carcinogenesis:prostate, cervical ,bladder, colorectal cancer
FGFR(1-4)
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Check points
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Fusion of TK to partner protein
ABLPDGFRFGFR1
FGFR3JAK2
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Bcr-Abl
C-Abl
Non receptor tyrosine kinase
Role:
Regulation of cell cycle,cellular response to genotoxic stress
Apoptosis neuronal development
Regulation :actin binding PI3 binding
C-Bcr localised in cytoplasm during mitosis(role in cell cycle regulation)
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Bcr-Abl
t(9:22)
Related to CML(chronic myeloid leukemia)
prevent apoptosis even in the absence of growth factors
Mitogenic signaling
Altered adhesion to matrix
TARGET-imatinim mesylate
mechanism
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Check points
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A serine threonine kinase:PKC
Response to
•Growth factors
•Hormones
•Drugs
11 related kinases
Unregulated in GIST
Diagnostic marker therapeutic target
Therapeutic targetsATP binding domain inhibitors Erbstatin
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Targeting Receptor
Monoclonal antibodies
• Herceptin, licensed for Her 2 receptor-positive
• Breast cancer
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Small molecular inhibitors
Various protein tyrosine kinase inhibitors
TYRosine PHOSphorylation INhibitors
tyrophosphins
Competitive with substrate(eg.Itaconic acid)
Competitive with ATP(Quinolines)(main thrust) ATP binding fold more
specific
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1. How many other kinase targets opened for exploration?
2. Majority of kinases remain largely uncharacterized.
A LOOK AHEAD
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Current challenges and future directions
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THANK YOU