This document provides an overview of receptor tyrosine kinases (RTKs) and their signaling pathways. It begins with an introduction to cell signaling and the different types of receptors, focusing on protein tyrosine kinases. RTKs are described as high-affinity cell surface receptors that activate upon ligand binding and recruit signal transduction proteins. The mechanisms of RTK activation and recruitment of proteins like Ras are explained. It further details how RTK activation of Ras leads to the Ras/MAP kinase signaling cascade, which regulates processes like cell division and differentiation. The relationships between different signaling pathways that can activate the Ras/MAP kinase cascade are also noted.

1. Presentation submitted to RGTU-UTD
(SOPS) on:-
TOPIC
:
Receptor Tyrosine Kinases (RTKs)
SUBMITTED BY:
DEEKSHA BOKRE
M.PHARM(Q.A)
Ist SEM

2. CONTENTS
 Introduction to cell signaling
 Types of Receptors
 Receptor tyrosine kinases (RTK)s
Mechanism action of insulin
Activation of RTKs via Ligand Binding
Recruitment of Signal Transduction Proteins to Activated Receptors
RTKs and Ras/MAP Kinase Signaling
RTK Activation of Ras
Ras Activation of MAP Kinase
MAP kinase cascade
 Relationship between Signaling Pathways

3. Introduction to cell signaling
• Many biological processes require various cells to work
together and to coordinate their activities. To make this
possible, cells have to communicate with each other, which is
accomplished by a process called cell signaling. Cell signaling
makes it possible for cells to respond in an appropriate manner
to a specific environmental stimulus.
• Cell signaling is also intimately involved in the regulation of
cell growth and division. This makes the study of cell
signaling crucially important for understanding how a cell can
lose the ability to control cell division and develop into a
malignant tumor.

4. Depending on the distance that the signaling molecule
has to travel, we can talk about three types of signaling:-
endocrine signaling
paracrine signaling
autocrine signaling

6. Types of Receptors
• There are a number of receptor classes that are
used in different signaling pathways.

7. • Protein-tyrosine kinases are enzymes that phosphorylate
specific tyrosine residues on protein substrates.
• Protein-tyrosine phosphorylation is a mechanism for signal
transduction that appeared with the evolution of
multicellular organisms.
• Over 90 different protein-tyrosine kinases are encoded by
the human genome. These kinases are involved in the
regulation of
growth, division, differentiation, survival, attachment to the
extracellular matrix, and migration of cells.

8. Protein-tyrosine kinases can be divided
in two groups:
Receptor proteintyrosine kinases
They activated directly by extracellular
growth and differentiation factors such as
epidermal growth factor (EGF) and
platelet-derived growth factor (PDGF) or
by metabolic regulators such as insulin
Non-receptor
protein-tyrosine
kinases
They are regulated indirectly by
extracellular signals and they control
processes as diverse as the immune
response, cell adhesion, and neuronal
cell migration.

9. Receptor tyrosine kinases (RTK)s
• Receptor tyrosine kinases (RTK)s are the highaffinity cell surface receptors for many
polypeptide growth factors, cytokines, and hormones.
• Receptor tyrosine kinases have been shown not only
to be key regulators of normal cellular processes but
also to have a critical role in the development and
progression of many types of cancer.

10. • RTK’s need to form dimer in plasma membrane.
• It add phosphate group to specific tyrosine residue of
other protein.
• It constitute of a super family distinct from the serine
and theronine kinases that operate in the reaction
cascade.
• It regulate cell growth and cell differentiation rather
than the control of intermediary metabolism because
insulin receptor has this enzymatic activity, it is
referred to as RTK.

11. • RTK’s do not phosphorylate every tyrosine in
substrate protein;they phosphorylate only those that
are present within certain amino seqences called as
phosphotyrosine motifs.
• The ligands for RTKs are soluble or membranebound peptide/protein hormones including
nerve growth factor (NGF), platelet-derived growth
factor (PDGF), fibroblast growth factor (FGF),
epidermal growth factor (EGF), and insulin.

12. Mechanism action of insulin
• The insulin receptor is a member of the tyrosine
kinase superfamily, generally involved in cell
growth and differentiation.
• The insulin receptor tyrosine kinase (RTK) is a
tetramer of two extracellular α subunits and two
transmembrane β subunits with a single
transmembrane region.
• α subunits bind insulin and induce a
conformational change in the β subunits,
activating their cytoplasmic kinase domain.
• Activated β
subunits phosphorylate one
another and a variety of insulin receptor
substrates (IRSs).

13. • RTKs phosphorylate only phosphotyrosine motifs ,After
phosphorylation these motifs have a high affinity for SH2
domains.
• Interaction of phosphotyrosine motifs with SH2 proteins cause
their conformational change so that they bind to other
proteins;faciliate transmission of signals

14. Insulin stimulation activates Protein Kinase B and MAP
kinase

15. • Most RTKs are monomers that only dimerize when bound to their
ligand. Dimerization activates the kinase activity and leads to
autophosphorylation, creating sites for interactions with specific
effectors. A key component of the RTK cascade is Ras.
• Ras:
 It is a small g protein that is held at the inner surface of the plasma
membrane by a lipid group,
 Ras also acts as both a switch and a molecular timer. Ras consists of
only a single small subunit.
 In its active form Ras stimulates effectors in signalling pathway.Ras
has a very weak GPTase activity.
 Mutation in Ras-GAP gene causes neurofibromatosis 1.

16. • Ras proteins are present in two different forms: an active GTPbound form and an inactive GDP-bound form.
• Ras-GTP binds and activates downstream signaling proteins.
Ras is turned off by hydrolysis of its bound GTP to GDP.
• These proteins are involved in the regulation of numerous
processes, including cell division, differentiation, gene
expression, cytoskeletal organization, vesicle trafficking, and
nucleocytoplasmic transport.
• Ras is mutated in 30% of human tumors. Most mutations
block hydrolysis keeping ras active and the cell in a
proliferative state.

17. • Grb2(growth factor receptor bound protein)
 It is an adaptor protein involved in signal
communication. In human it is encoded by GRB2 gene.
• Sos
 It is a guanine nucleotide exchange factor for Ras.
• Raf
Ras-GTP recruits raf, which becomes activated as a
protein kinase and initiates the MAP kinase cascade

18. Activation of RTKs via Ligand
Binding
 The binding of ligand activates the kinase domains which crossphosphorylate the two monomers of the dimeric receptor.
Phosphorylation first occurs at a regulatory site known as the
activation lip.
 Phosphorylation of the lip causes conformational changes that allow
the kinase domain to phosphorylate other tyrosine residues in the
receptor and in signal transduction proteins.

20. Recruitment of Signal Transduction
Proteins to Activated Receptors
 Signal transduction system proteins interact with
phosphorylated RTKs via phosphotyrosine binding
domains(PTB) and SH2 (Src homology domain-2) within
signal transduction proteins such as the multi-docking protein
known as the insulin receptor substrate-1 (IRS-1) perform this
function
 The binding of signaling proteins either directly to the receptor
or to IRS-1 allows them to be phosphorylated by the receptor.
Some of these signaling proteins are involved in activation of
the Ras GTPase .
 Some such as phosphatidylinositol-3 kinase (PI-3 kinase)
participate in lipid-mediated signaling pathways.

22. RTKs and Ras/MAP Kinase
Signaling
• Nearly all RTKs signal via Ras/MAP kinase pathways.
• They also may signal via other pathways. For example, the
insulin receptor uses the Ras/MAP kinase pathway to regulate
gene expression and the PI-3 kinase pathway to regulate
enzyme activity (e.g., glycogen synthase).
•
RTK-Ras/MAP kinase signaling controls cell division,
differentiation, and metabolism.

23. 
Ras once activated,it propagates signaling further inside the
cell via a kinase cascade that culminates in the activation of
members of the MAP kinase family.

MAP kinases phosphorylate TFs that regulate genes
involved in the cell cycle and in differentiation.

Mutant RTKs or Ras/MAP kinase signaling proteins are
associated with nearly all cancers.

Dominant Ras mutations that block GAP binding and lock
Ras in the "on" state promote cancer.

24. RTK Activation of Ras
Step 1
EGF binding causes receptor dimerization and autophosphorylation on
cytosolic tyrosines.
Step 2
The adaptor protein GRB2 binds receptor phosphotyrosine residues via its
SH2 domain. GRB2 contains SH3 domains that allow the GEF protein known
as Sos to bind to the membrane complex. Sos then recruits Ras to the
complex. In the last step of Ras activation
Step 3
Sos promotes GTP exchange for GDP on Ras. The activated Ras-GTP
complex then dissociates from Sos. The active form of Ras then activates the
MAP kinase portion of the signaling pathway

28. Ras Activation of MAP Kinase
• Ras activates MAP kinase via a phosphorylation cascade that
proceeds from Ras to Raf kinase, to MEK kinase, and finally
to MAP kinase . MAP kinase then dimerizes and enters the
nucleus

30. MAP kinase cascade
(Mitogen-Activated Protein: activated by a mitosisstimulating growth factor)

31. Relationship between Signaling
Pathways
G protein-coupled receptors, RTKs and
integrins can all relay signals that result in
the recruitment to the membrane of the
adaptor protein Grb2 and the activation of
Ras and the MAP kinase cascade.

32. Do not choose for any one,what
you do not choose for
yourself.....!!!
Thank you....