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CCELL CELL SIGNALING
[ION CHANNEL LINKED RECEPTOR
&
ENZYME LINKED RECEPTOR]
Guided by
Dr. Niraj Agarwal Sir.
Presented by
Ritima Mishra
Msc 3rd sem
Roll No. -25
INTRODUCTION
What is cell signaling?
All cells receive and respond to
signals from their surroundings.
Signaling molecules, which are
released by signal producing cells,
reach and transfer biological signals to
their target cells to initiate specific
cellular responses.
Stages of cell signaling
Receiving.
Transduction
Response.
What is ligand ?
 ligands are signaling
molecule.
Produced by signal producing
cell to generate response n
target cell.
Ligands may be–
cytokine hormone
steroid Growth factor.
polypeptide
What is receptor?
Receptors are Glycoprotein
on the cell surface.
Receptor helps to receive the
signals from outside and
generate responses
intracellularly.
Types of Receptor –
A.Intracellular receptor.
B.Cell surface receptor.
i)GPCR.
ii)Ion-Channel linked receptor.
iii)Enzyme linked receptor.
Signaling
Signaling molecule
Bind to receptor of
target cell.
Intracellular response by
internal molecule.
Biological effect
Ion Channel Linked Receptor
 Also known as cell membrane bound receptor, Ligand gated channel,
transmitter gated ion channel, ionotropic receptor.
 Here receptor is multipass protein.
 Ion channel linked receptor bind a ligand and open a channel through the
membrane that allows specific ions to pass through.
Mechanism –
 When a ligand bind with the extracellular region of the channel there is a
conformational change in the protein structure that allows ions such as
Na+,Ca+,Mg+,K+ and H+ to pass through.
 For example- Ligand gated channel for NTM Acetylcholine.
 NTM or peptide hormone can act as a ligand.
 As two molecules of acetylcholine binds with the receptor .
 The conformation of the receptor changed and gate is open, allows
the entry of many ions(cations specially) and small molecule.
ENZYME LINKED RECEPTOR
 Enzyme linked receptor are second major type of cell surface receptor.
 are single pass membrane protein.
 Having their ligand binding site outside the cell and their catalytic side inside.
 Great majority are protein kinases.(associated or itself a protein kinase).
 Kinases can phosphorylate specific protein in the target cell which again can
phosphorylate downstream proteins .
 An enzyme linked receptor also known as catalytic receptor , is a transmembrane
receptor.
 Wherer the binding of an extracellular ligand causes enzymatic activity on the
intracellular side.
• Receptor may have –
i)The receptor with intracellular
domain that are associated with
an enzyme.
ii)The receptor with intracellular
domain that itself act as an
enzyme.
There are 3 types of enzyme –linked receptor --
-
i)Receptor –Tyrosine kinase.
ii)Tyrosine-Kinase associated receptor .
iii)Receptor Serine/ Threonine kinase.
i) Receptor Tyrosine kinase-
 Receptor tyrosine kinases (RTK) are the high affinity cell surface receptor for
many polypeptides( growth factor , cytokinine and hormones).
 Receptor tyrosine kinase have been shown not only to be key regulator of
normal cellular processess but also have a critical role in the development and
progression of many types cancer.
 Mutation in receptor protein kinase leads to activation of receptor in absence
of ligand also and effect protein expression.
 Kinase enzymes that specifically phosphorylate the amino acid, tyrosine, termed
as tyrosine kinase.
 Ligand for RTK-
Nerve growth
factor
Platelet growth
factor
Fibroblast
Growth Factor
Hepatocyte
growth factor
Insulin growth
factor
Epidermal
growth factor
Structure of RTK
Mode of action of RTK-
 When a growth factor binds to the extracellular domain of RTK,
dimerization happen with the adjacent RTK.
 Which enables the two cytoplasmic domains to cross phosphorylate the
tyrosine residue of each other .
 This cross phosphorylation is called autophosphorylation.
• There are 3 major pathways can transduce a
signal from activated RTK:-
1.Ras-MAP kinase (MAPK also called as ERK-Extracellular signal
regulated kinase)
2.IP3/DAG Pathway.
3.PI-3 kinase pathway/AKT
a.mTOR
b.Insulin signaling.
What is a Ras?
• Belongs to GTPase family.
• Ras is monomeric g –protein(GTPase)
switch protein.
• Ras is a guanosine-nucleotide –
binding protein.
• Ras has intrinsic GTPase activity.
• Which means that protein on its own
will hydrolyze a bound GTP molecule
into GDP.
• When Ras is active,it turn on genes
involved in cell growth,differentiat-
- ion and survival.
• It anchored in the plasmamembrane.
• Mutation of it can cause cancer.
What is MAP kinase?
•MAPK-Mitogen –
activating protein kinase .
•It is a type of protein
kinase that is specific to the
amino acids serine and
threonine.
MODE OF ACTION :
a. Ras-MAP Kinase Pathway :-
Some important terms of
Ras-MAP
Kinase
Pathway:-
 SOS-Son of Sevenless.(nulcleotide
exchange factor)
GRB2-Growth Factor Binding 2
Raf-Serine/Thr kinase.(MAPKKK)
MEK-Serine/thr kinase/tyr kinase(MAPKK).
Elk-1-Transcription factor activating protein.
Fos-june-transcription factor
b.IP3-DAG Pathway-
• Some important terms of
IP3-DAG
Pathway IP3- Inositol 1,4,5 triphosphate.
PIP2-Phosphotidylinositol 4,5 –
biphosphate.
DAG-Diacylglycerol.
PKC-Protein Kinase C.
c.PI-3 kinase pathway/AKT-
• Some important terms of PI-3-Kinase
pathway
PI-3:- Phosphatidylinositol 3 Kinase.
PIP2:-Phosphatidylinositol-4,5-
biphosphate
PIP3:-Phosphatidylinositol -3,4,5-
biphosphate
PKB:-Protein Kinase B.
PDK-pkb Dependent Kinase 2
i) 1- mTOR pathway:-
 mTOR- Mammalian Target of Rapamycin.
 Extracellular signal require for the animal cell to grow ,divide and
survive.
 TOR- serine threonine kinase.
 Tor has two multiprotein complex-
Complex 1(mTORC1)
It has Raptor protein.
Sensitive to Rapamycin
.
mTORC1 promote protein
synthesis by phosphorylating
the eIF4E-Binding Protein by
making the Eif4e free for
translation.
Complex2 (mTORC2)
It has Rictor protein.
Insensitive to Rapamycin.
Rictor help in activation of
AKT and it regulate the
actin cytoskeleton via Rho
family GTPase.
• mTOR Pathway-
If extracellular growth
factor on RTK.
Activate PIP-3 Kinase.
Activate AKT/PKB
Activate mTORc1
TSC-2(GAP)
Rheb-GTP
Add phosphate at
eIF4E-BP
eEF4E active Protein synthesis
ii)Insulin signaling pathway-
 It’s a type of peptide hormone secreted by pancreati cells (β-langerhans
cells).
 Receptor of Insulin- Dimer (Inactive) and tetramer(active).
 Insulin receptor synthesis to maintain the blood glucose level.
 The receptor of insulin may present at liver,muscles,adipose tissue(store
glucose).
 Insulin signaling pathway – Ras dependent
Ras independent.
Ras dependent and Ras independent
ii)Tyrosine kinase associated receptor –
 Rather than processing intrinsic enzymatic activity,many enzymes linked
receptor act by stimulating intracellular protein tyrosine kinase with which
they are non-covalently associated.
 N terminal –Ligand binding domain.
 C terminal –cytosolic domain of the tyrosine kinase associated with
receptor get activated after binding with ligand.
 Enzyme cytosolic tyrosine kinase—JAK (Janus kinase).
 Maximum receptor are antigen ,peptide,(GH, prolactin),interlukins.
JAK-STAT Pathway
• Some important terms of JAK-STAT pathway-
JAK:-Janus kinase.
STAT:-Signal Transducer and Activator
of Transcription.
iii)Receptor Serine/Threonine kinase-
 These receptors are single pass transmembrane protein.
 There are two classes of serine/threonine kinase of receptor-TypeI
-TypeII
 Ligands are- TGF-β, BMPs ,Activins.
 This receptor donot active in homodimer form active in heterodimer form.
 Protein from this group participate in 7 metabolic pathways-
1.MAPK 2.Cytokine –cyt receptor interaction. 3.TGF-β 4.Adhrens junction.
5.Colorectal cancer. 6.pancreatic cancer. 7.Chronic myeloid leukemia.
Serine/ threonine kinase Pathway-
• Some important terms of Serine/ thr kinase
Receptor
Pathway
SMAD:-mediators of TGF-β
signal transduction.
Conclusion
 A signal is an entity that codes or conveys information.
 The ability of cells to perceive and correctly respond to their
microenvironment is the basis of development, tissue repair,
and immunity as well as normal tissue homeostasis.
 Errors in signaling interactions and cellular information
processing may cause diseases such as cancer, autoimmunity
and diabetes.
THANK YOU

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Cell signaling by Ritima mishra

  • 1. CCELL CELL SIGNALING [ION CHANNEL LINKED RECEPTOR & ENZYME LINKED RECEPTOR] Guided by Dr. Niraj Agarwal Sir. Presented by Ritima Mishra Msc 3rd sem Roll No. -25
  • 2. INTRODUCTION What is cell signaling? All cells receive and respond to signals from their surroundings. Signaling molecules, which are released by signal producing cells, reach and transfer biological signals to their target cells to initiate specific cellular responses. Stages of cell signaling Receiving. Transduction Response. What is ligand ?  ligands are signaling molecule. Produced by signal producing cell to generate response n target cell. Ligands may be– cytokine hormone steroid Growth factor. polypeptide What is receptor? Receptors are Glycoprotein on the cell surface. Receptor helps to receive the signals from outside and generate responses intracellularly.
  • 3. Types of Receptor – A.Intracellular receptor. B.Cell surface receptor. i)GPCR. ii)Ion-Channel linked receptor. iii)Enzyme linked receptor.
  • 4. Signaling Signaling molecule Bind to receptor of target cell. Intracellular response by internal molecule. Biological effect
  • 5. Ion Channel Linked Receptor  Also known as cell membrane bound receptor, Ligand gated channel, transmitter gated ion channel, ionotropic receptor.  Here receptor is multipass protein.  Ion channel linked receptor bind a ligand and open a channel through the membrane that allows specific ions to pass through. Mechanism –  When a ligand bind with the extracellular region of the channel there is a conformational change in the protein structure that allows ions such as Na+,Ca+,Mg+,K+ and H+ to pass through.
  • 6.  For example- Ligand gated channel for NTM Acetylcholine.  NTM or peptide hormone can act as a ligand.  As two molecules of acetylcholine binds with the receptor .  The conformation of the receptor changed and gate is open, allows the entry of many ions(cations specially) and small molecule.
  • 7. ENZYME LINKED RECEPTOR  Enzyme linked receptor are second major type of cell surface receptor.  are single pass membrane protein.  Having their ligand binding site outside the cell and their catalytic side inside.  Great majority are protein kinases.(associated or itself a protein kinase).  Kinases can phosphorylate specific protein in the target cell which again can phosphorylate downstream proteins .  An enzyme linked receptor also known as catalytic receptor , is a transmembrane receptor.  Wherer the binding of an extracellular ligand causes enzymatic activity on the intracellular side.
  • 8. • Receptor may have – i)The receptor with intracellular domain that are associated with an enzyme. ii)The receptor with intracellular domain that itself act as an enzyme.
  • 9. There are 3 types of enzyme –linked receptor -- - i)Receptor –Tyrosine kinase. ii)Tyrosine-Kinase associated receptor . iii)Receptor Serine/ Threonine kinase.
  • 10. i) Receptor Tyrosine kinase-  Receptor tyrosine kinases (RTK) are the high affinity cell surface receptor for many polypeptides( growth factor , cytokinine and hormones).  Receptor tyrosine kinase have been shown not only to be key regulator of normal cellular processess but also have a critical role in the development and progression of many types cancer.  Mutation in receptor protein kinase leads to activation of receptor in absence of ligand also and effect protein expression.  Kinase enzymes that specifically phosphorylate the amino acid, tyrosine, termed as tyrosine kinase.  Ligand for RTK- Nerve growth factor Platelet growth factor Fibroblast Growth Factor Hepatocyte growth factor Insulin growth factor Epidermal growth factor
  • 12. Mode of action of RTK-  When a growth factor binds to the extracellular domain of RTK, dimerization happen with the adjacent RTK.  Which enables the two cytoplasmic domains to cross phosphorylate the tyrosine residue of each other .  This cross phosphorylation is called autophosphorylation.
  • 13. • There are 3 major pathways can transduce a signal from activated RTK:- 1.Ras-MAP kinase (MAPK also called as ERK-Extracellular signal regulated kinase) 2.IP3/DAG Pathway. 3.PI-3 kinase pathway/AKT a.mTOR b.Insulin signaling.
  • 14. What is a Ras? • Belongs to GTPase family. • Ras is monomeric g –protein(GTPase) switch protein. • Ras is a guanosine-nucleotide – binding protein. • Ras has intrinsic GTPase activity. • Which means that protein on its own will hydrolyze a bound GTP molecule into GDP. • When Ras is active,it turn on genes involved in cell growth,differentiat- - ion and survival. • It anchored in the plasmamembrane. • Mutation of it can cause cancer. What is MAP kinase? •MAPK-Mitogen – activating protein kinase . •It is a type of protein kinase that is specific to the amino acids serine and threonine.
  • 15. MODE OF ACTION : a. Ras-MAP Kinase Pathway :-
  • 16. Some important terms of Ras-MAP Kinase Pathway:-  SOS-Son of Sevenless.(nulcleotide exchange factor) GRB2-Growth Factor Binding 2 Raf-Serine/Thr kinase.(MAPKKK) MEK-Serine/thr kinase/tyr kinase(MAPKK). Elk-1-Transcription factor activating protein. Fos-june-transcription factor
  • 18. • Some important terms of IP3-DAG Pathway IP3- Inositol 1,4,5 triphosphate. PIP2-Phosphotidylinositol 4,5 – biphosphate. DAG-Diacylglycerol. PKC-Protein Kinase C.
  • 20. • Some important terms of PI-3-Kinase pathway PI-3:- Phosphatidylinositol 3 Kinase. PIP2:-Phosphatidylinositol-4,5- biphosphate PIP3:-Phosphatidylinositol -3,4,5- biphosphate PKB:-Protein Kinase B. PDK-pkb Dependent Kinase 2
  • 21. i) 1- mTOR pathway:-  mTOR- Mammalian Target of Rapamycin.  Extracellular signal require for the animal cell to grow ,divide and survive.  TOR- serine threonine kinase.  Tor has two multiprotein complex- Complex 1(mTORC1) It has Raptor protein. Sensitive to Rapamycin . mTORC1 promote protein synthesis by phosphorylating the eIF4E-Binding Protein by making the Eif4e free for translation. Complex2 (mTORC2) It has Rictor protein. Insensitive to Rapamycin. Rictor help in activation of AKT and it regulate the actin cytoskeleton via Rho family GTPase.
  • 22. • mTOR Pathway- If extracellular growth factor on RTK. Activate PIP-3 Kinase. Activate AKT/PKB Activate mTORc1 TSC-2(GAP) Rheb-GTP Add phosphate at eIF4E-BP eEF4E active Protein synthesis
  • 23. ii)Insulin signaling pathway-  It’s a type of peptide hormone secreted by pancreati cells (β-langerhans cells).  Receptor of Insulin- Dimer (Inactive) and tetramer(active).  Insulin receptor synthesis to maintain the blood glucose level.  The receptor of insulin may present at liver,muscles,adipose tissue(store glucose).  Insulin signaling pathway – Ras dependent Ras independent.
  • 24. Ras dependent and Ras independent
  • 25. ii)Tyrosine kinase associated receptor –  Rather than processing intrinsic enzymatic activity,many enzymes linked receptor act by stimulating intracellular protein tyrosine kinase with which they are non-covalently associated.  N terminal –Ligand binding domain.  C terminal –cytosolic domain of the tyrosine kinase associated with receptor get activated after binding with ligand.  Enzyme cytosolic tyrosine kinase—JAK (Janus kinase).  Maximum receptor are antigen ,peptide,(GH, prolactin),interlukins.
  • 27. • Some important terms of JAK-STAT pathway- JAK:-Janus kinase. STAT:-Signal Transducer and Activator of Transcription.
  • 28. iii)Receptor Serine/Threonine kinase-  These receptors are single pass transmembrane protein.  There are two classes of serine/threonine kinase of receptor-TypeI -TypeII  Ligands are- TGF-β, BMPs ,Activins.  This receptor donot active in homodimer form active in heterodimer form.  Protein from this group participate in 7 metabolic pathways- 1.MAPK 2.Cytokine –cyt receptor interaction. 3.TGF-β 4.Adhrens junction. 5.Colorectal cancer. 6.pancreatic cancer. 7.Chronic myeloid leukemia.
  • 30. • Some important terms of Serine/ thr kinase Receptor Pathway SMAD:-mediators of TGF-β signal transduction.
  • 31. Conclusion  A signal is an entity that codes or conveys information.  The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue homeostasis.  Errors in signaling interactions and cellular information processing may cause diseases such as cancer, autoimmunity and diabetes.