Protein kinases _ Role in cell signaling _ implication in human

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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: 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                          Effector enzymes
 MAP kinase,
• Transcription factors
– Bind consensus sequence on
        promoter
– May form complexes
– May itself be transcribed
 following cellular activation
               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:
                           Related pathologies
                           Check points

Serine threonine kinases     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     Overexpression of
         receptor or ligand
c-KIT
FGFR3
                   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
                                C-KIT
expression
                                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   prevent apoptosis even in the absence of
c   growth factors
h
a   Mitogenic signaling
n
i   Altered adhesion to matrix
s
m
    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

				
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