SPEAKER :DR.V.

SNEHAL

CHAIR PERSON : DR.EZHIL ARASI(PROF) MODERATOR : DR.CHANDRA SHEKAR(ASSOC.PROF)

 A signal transduction pathway is a series of steps by which a

signal on a cells surface is converted into a specific cellular response.

Activated by the binding of ligands such as growth factors and

cytokines to specific receptors.

According to the source of the ligand and the location of its

receptors three general modes of signaling, named autocrine, paracrine, and endocrine, can be distinguished.

Sutherland suggested that cells receiving signals went through three processes Reception Transduction Response
Key Steps in Signal Transduction Release of the primary messenger Reception of the primary messenger Delivery of the message inside the cell by the second messenger

Figure 11.6-3

EXTRACELLULAR FLUID 1 Reception Receptor

CYTOPLASM Plasma membrane 2 Transduction 3 Response

Activation of cellular response

Relay molecules in a signal transduction pathway

Signaling molecule

 Although single receptor molecules can transduce some signals

upon ligand binding, signaling typically involves clustering of two or more receptor molecules by the ligand.
Signal transduction usually involves multiple steps
Multistep pathways can amplify a signal: A few molecules can

produce a large cellular response

Multistep pathways provide more opportunities for

coordination and regulation of the cellular response

 The molecules that relay a signal from receptor to response are

mostly proteins
The receptor activates another protein, which activates another,

and so on, until the protein producing the response is activated

At each step, the signal is transduced into a different form,

usually a shape change in a protein

 In many pathways, the signal is transmitted by a cascade of

protein phosphorylations
Protein kinases transfer phosphates from ATP to protein, a

process called phosphorylation

Protein phosphatases remove the phosphates from proteins, a

process called dephosphorylation

This phosphorylation and dephosphorylation system acts as a

molecular switch, turning activities on and off or up or down, as required

 Consequences of second messengers

Signal may be amplified Often free to diffuse throughout cell Common second messengers may create cross talk

 The binding between a signal molecule (ligand) and

receptor is highly specific

A shape change in a receptor is often the initial

transduction of the signal

Most signal receptors are plasma membrane proteins

Receptors and Signal Transduction Pathways

The binding of a ligand to its receptor triggers a series of

events by which extracellular signals are transduced into the cell resulting in changes in gene expression
There are three main types of membrane receptors G protein-coupled receptors Receptor tyrosine kinases Ion channel receptors

diagram

Receptor with Tyrosine Kinase

Ligand : EGF, TGF-, HGF, PDGF, VEGF, FGF, c-KIT

ligand, and insulin.

Extracellular domain Transmembrane Cytoplasmic tail

MAP kinase pathway

Examples
90% of pancreatic adenocarcinomas and cholangiocarcinomas

contain a RAS point mutation, 50% of colon, endometrial, and thyroid cancers 30% of lung adenocarcinomas and myeloid leukemias.
Colon and pancreas---KRAS mutations Bladder tumors --- HRAS mutations. hematopoietic tumors ---NRAS mutations.

RAS mutations are infrequent in certain other cancers, such as

those arising in the uterine cervix or breast.

 Abrogation of RAS function blocks the proliferative response

to EGF, PDGF, and CSF-1 Disabling mutation of neurofibromin 1, a GAP, is associated with the inherited cancer syndrome familial neurofibromatosis type 1 . Mutations in BRAF, one of the members of the RAF family, have been detected in more than 60% of melanomas and in more than 80% of benign naevi Because RAS is so frequently mutated in human cancers, much effort has been spent to develop anti-RAS modalities of targeted therapy

 Mutated/overexpessed receptor tyrosine kinases

often observed in tumors

Some EGFR can dimerize and send growth signal

even in absence of EGF

Cetuximab (Erbitux) an antibody used therapeutically

to prevent dimerization
Her2 overexpressed in ~30% of breast cancers

IP3-kinase and PI3K kinase

PLC Phosphorylates

phospholipids

Phospholipids
IP3

Activate kinase

Akt(protein kinase B)

Ca and DAG
Serine threonine kinase

Proliferation and cell

survival

protein kinase C factors

Inhibition of apoptosis

Activate transcription

G protein coupled receptors and cAMP pathway

Ligands : chemokines, vasopressin, serotonin,

histamine, epinephrine and norepinephrine, calcitonin, glucagon, PTH, corticotrophin and rhodopsin 7 transmembrane helices Largest family of receptors Target for drugs Activation of G protein GDP ---------GTP

diagram

cAMP
cAMP activates protein kinase A (PKA)
Depends on type of cell

In skeletal muscle and liverGlycogenolysis Cardiac muscle- Strengthens muscle contraction Smooth muscle- Inhibits contraction Intestinal epithelium- Movement of salt and water into gut

Protein kinase A

Vision and olfactory sensing Phosphorylates ser ine & threonine Activate proteins Activate genes!

Inherited defects involving G protein coupled receptor

transduction pathway Retinitis pigmentosa Corticotrophin defeciencies Hyperparathyroidism

Receptors lacking TK activity

Ligands : IL-2,IL-3 . interferons , , . EPO.

Granulocyte colony stimulating factor, growth hormone and prolactin.

JAK protein is activated which in turn activates

cytoplasmic transcription factor STAT-gene transcription.

Alterations in Nonreceptor Tyrosine Kinases

As with receptor tyrosine kinases, in some instances the

mutations take the form of chromosomal translocations or rearrangements that create fusion genes encoding constitutively active tyrosine kinases
Eg: CML ---BCR-ABL------------ tyrosine kinase Treatment of CML ---Gleevec --imatinib mesylate---

a designer drug with low toxicity and high therapeutic efficacy that inhibits the BCR-ABL kinase.

 Point mutations in tyrosine kinase JAK 2

The aberrant JAK2 kinase in turn activates transcription factors

of the STAT family, which promote the growth factor independent proliferation and survival of the tumor cells.
Eg: Several myeloproliferative disorders, Polycythemia vera

and Primary Myelofibrosis

Transcription Factors
Just as all roads lead to Rome, all signal transduction pathways

converge to the nucleus. The ultimate consequence of signaling through oncogenes like RAS or ABL is inappropriate and continuous stimulation of nuclear transcription factors that drive growth-promoting genes. Transcription factors contain specific amino acid sequences or motifs that allow them to bind DNA or to dimerize for DNA binding. A host of oncoproteins, including products of the MYC, MYB, JUN, FOS, and REL oncogenes, are transcription factors that regulate the expression of growth-promoting genes, such as cyclins. MYC is most commonly involved in human tumors.

Summary
When signal molecules are present, they induce

signal transduction pathways that amplify the initial signal and cause changes in effector molecules Important second messengers include Ca2+, cAMP, cGMP, IP3, & DAG The seven-transmembrane-helix (7TM) receptor family is very important in signal transduction pathways The -adrenergic receptor, rhodopsin, & angiotensin II receptor are members of this family

Summary
Phosphorylation cascades important to many signal

transduction processes Protein kinase can be part of the receptor. EGF also binds to a receptor that has a tyrosine kinase as one of its subunits Kinase activity leads to activation of Ras, which leads to phosphorylation of transcription factors and changes in gene expression EGF signaling terminated by phosphatases and hydrolysis of GTP by Ras

Summary
Signal-transduction pathways often share common

elements E.g., protein kinases & second messengers Defects in signal-transduction pathways can lead to cancer and other diseases Lead to errors in growth signals Lead to G proteins being perpetually on or off Monoclonal antibodies and kinase inhibitors used as therapeutic agents

References
ROBBINS AND COTRAN PATHOLOGIC BASIS OF

DISEASE, 8/E
Harper's Illustrated Biochemistry 27th Edition

www.studentconsult.com

 Thank you

 Pertussis toxin
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allergy of histamine

Cholera toxin

Ribosylation of Arg of G G -ATP

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G -ADP
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Pertussis toxin
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cAMP allergy of histamine