Tyrosine kinase linked receptors

properties and various functions of tyrosine-kinase receptors.

1. TYROSINE-KINASE LINKED RECEPTORS RTK FAIDURAHMAN KALATHINGAL 1 M.Sc BOTANY 19PBO 118

2. INTRODUCTION  Protein kinases are a group of enzymes that possess a catalytic subunit that transfers the gamma (terminal) phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function.

3. HOW SIGNAL IS PASS INSIDE THE CELLL? Signal Transduction - a basic process involving the conversion of a signal from outside the cell to a functional change within the cell

4. SIGNAL MOLECULES & RECEPTORS  A cell targeted by a particular chemical signal has a receptor protein that recognizes the signal molecule. When ligands (small molecules that bind specifically to a larger molecule) attach to the receptor protein, the receptor typically undergoes a change in shape.

5. CATEGORIES OF PROTEIN KINASES Kinases that specifically phosphorylate tyrosine residues . Kinases that phosphorylate serine and threonine residues. Kinases with activity toward all three residues.

6. SIGNALING THROUGH ENZYME-LINKED CELL-SURFACE RECEPTORS Six classes: 1. Receptor tyrosine kinases 2. Tyrosine kinase -associated receptors 3. Receptor like tyrosine phosphatases 4. Receptor serine/ threonine kinases 5. Receptor guanylyl cyclases 6. Histidine - kinase -associated receptors

7. WHAT IS A TYROSINE KINASE? A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a tyrosine residue in a protein. Approximately 2000 kinases are known. Among them 90 are tyrosine kinases . The tyrosine kinases are divided into two main families: The trans membrane receptor- linked kinases . Those that are cytoplasmic proteins.

8. TYPES OF TYROSINE KINASES Tyrosine kinases can be further subdivided into: 1. Receptor tyrosine kinases eg : EGFR, PDGFR, FGFR 2. Non-receptor tyrosine kinases eg : SRC, ABL, FAK and Janus kinase

9. RECEPTOR 58 receptor tyrosine kinases (RTKs) are known, grouped into 20 subfamilies.These are involved in: growth Differentiation Metabolism Adhesion Motility death

10. NON-RECEPTOR/ CYTOPLASMIC 32 cytoplasmic protein tyrosine kinases are also known as PTKs. First non-receptor tyrosine kinase identified was the v- src oncogenic protein.

11. RECEPTOR TYROSINE KINASE RTK is like a communication device, since these membrane proteins transmit signals from the cell’s environment into the cell. Tyrosine- kinase receptor is effective when the cell needs to regulate and coordinate a variety of activities and trigger several signal pathways at once.

12. Mechanism of PDGF signal transduction   Activated RTKs transmit signal to Ras protein Ras transduces signal to downstream serine-threonine kinases Ultimate activation of MAP kinase Activation of transcription factors

13. Receptor Dimerization and Kinase Activation

14. RTK

15. Tyrosine Protein Phosphorylation Eukaryotic cells coordinate functions through environmental signals - soluble factors, extracellular matrix, neighboring cells. Membrane receptors receive these cues and transduce signals into the cell for appropriate response. Tyrosine kinase signalling is the major mechanism for receptor signal transduction. Tyrosine protein phosphorylation is rare (1%) relative to serine/ threonine phosphorylation . TK pathways mediate cell growth, differentiation, host defense, and metabolic regulation. Protein tyrosine phosphorylation is the net effect of protein tyrosine kinases (TKs) and protein tyrosine phosphatases (PTPs ).

16. Ras Monomeric GTPase switch protein Its activation is enhanced by GEF GDP-GTP exchange Deactivation of Ras-GTP complex requires GAP, which increases intrinsic GTPase activity 100 fold Lifetime of Ras-GTP is higher than that of G  Ras is a small protein (170 aa. Vs 300 aa of G  ) G  has a domain that functions like GAP Mutant ras proteins are associated with many cancers Mutant ras can bind GTP but can not hydrolyze it, and thus remain constitutively in “on” state Most oncogenic ras proteins contain a mutation in codon 12 (Gly) This blocks the binding of GAP to ras, and prevents GTP hydrolysis

17. Ligand-bound RTKs activate ras! How? Two cytosolic proteins are involved: GRB2, Sos SH2 domain in GRB2 binds to a P*-tyrosine residue in the activated receptor Two SH3 domains of GRB2 bind to and activate Sos Sos is GEF protein and convert inactive GDP-ras into active GTP-ras Developmental studies elucidated the role of GRB2 and Sos in linking RTKs to ras activation

18. MECHANISM OF RTK