Protein kinases : Role in cell signaling &
implication in human pathologies
Jayanti Tokas1, Rubina Begum1, Shalini Jain2 and Hariom
Yadav2
1Department
2
of Biotechnology, JMIT, Radaur
NIDDK, National Institute of Health, Bethesda,MD20892, USA
Email: yadavhariom@gmail.com
Protein Kinase
30% of all proteins may be modified
518 protein kinase genes=human kinome space
20% of all eukaryotic genes(human genome project)
Approx 30=tumor suppressor
218 genes=human diseases
Approx 100 dominant oncogenes
Kinases
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
‘signal’ • Viability/survival
• Homeostasis
• Effector function (e.g. cytotoxicity, cytokine production)
• Cell death
Signal Transduction
and Kinase Pathways
Adaptor proteins
Nucleus
MAP kinase,
• Transcription factors
– Bind consensus sequence on
promoter
– May form complexes
– May itself be transcribed
following cellular activation
Effector enzymes
Classification
On the basis of amino acid :
 Tyrosine kinases, Receptor (EGFR,FGFR,PDGFR)
non receptor (JAK,src,Abl,MAPK)
 Serine threonine (PKC, Plk,Rho Kinases)
Tyrosine kinase
structure
function:
Serine threonine kinases
Related pathologies
Check points
Related pathology
Check points
Structure
Bioblar structure
N and c
N-beta sheets
C-alpha helix
ATP bind-cleft at
intetrsection
How they function:
Mechanisms of Activation of Normal TKs.
May
oligomerise
Differentiation
Motility
Proliferation
survival
Control
Autoinhihibitory transmembrane interactions
cytoplasmic juxtamembrane region further inhibits the
enzyme by interacting with the kinase domain
Autophosphorylation---. reorient critical amino acid
residues increasing catalytic activity
inhibitor proteins and lipids
IF CONTROL LOST
Loss of
function
Gain of function
Mechanisms of TK Dysregulation
oPDGF
EGF
VEGF
FGF
KL
oPDGF
R
EGFR
HER2
c-KIT
FGFR3
Overexpression of
receptor or ligand
EGFR
Superfamily with 4 receptors
C-ERBB
C-ERBB2
C-ERBB3
C-ERBB4
Cell proliferation
Inhibition of apoptosis
Angiogenesis
Cell motility
metastasis
Carcinogenesis:
colorectal
cancer, lung cancer(enhanced responsiveness),glioblastoma
multiforme(constitutive active)
Dysregulation
Cell proliferation inh of apoptosis angiogenesis metastasis
Over expressed & mutated
Deletions(exon 2-7:alternative splicing)
or point mutations(Ile654Val)
Check points
FLT3
Mutation in receptor tyrosine
kinase causing constitutive
expression
C-KIT
PDGFR
EGFR
HER2
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
• Glioblastoma
• Atherosclerosis
• Pathological conditions:del(4q12) ; t(4;22)
• Adenocarcinoma
• Breast
• Colon
• Prostate
• Stomach
FGFR(1-4)
 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
Check points
Fusion of TK to partner protein
ABL
PDGFR
FGFR1
FGFR3
JAK2
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)
Bcr-Abl
t(9:22)
Related to CML(chronic myeloid leukemia)
m
e
c
h
a
n
i
s
m
prevent apoptosis even in the absence of
growth factors
Mitogenic signaling
Altered adhesion to matrix
TARGET-imatinim mesylate
Check points
A serine threonine kinase:PKC
Response to
•Growth factors
•Hormones
•Drugs
11 related kinases
Unregulated in GIST
Diagnostic marker therapeutic
target
Therapeutic targets ATP binding domain inhibitors Erbstatin
Targeting Receptor
Monoclonal antibodies
• Herceptin, licensed for Her 2 receptor-positive
• Breast cancer
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
A LOOK AHEAD
1. How many other kinase targets opened for
exploration?
2. Majority of kinases remain largely uncharacterized.
Current challenges and future directions
THANK YOU