Cell signaling is a complex process by which cells communicate with each other to regulate various cellular activities, including growth, differentiation, metabolism, and apoptosis (cell death). Signaling molecules, such as hormones, growth factors, and neurotransmitters, bind to specific receptors on the cell surface or inside the cell, initiating a cascade of events that ultimately lead to a cellular response. There are several signaling pathways involved in cell signaling, including the Ras-MAPK pathway and the JAK-STAT pathway. Both the Ras-MAPK pathway and the JAK-STAT pathway are critical for normal cellular function, and dysregulation of these pathways can lead to various diseases, including cancer and inflammatory disorders.

1. PRESENTED BY:
SONAL SINGH SHRIVAS

2. SYNOPSIS
Introduction to cell signaling
Components of cell signaling
(I) Signaling molecule or Ligand
(II) Receptor
(i) Intracellular receptors
(ii) Extracellular receptors
(A) G-protein coupled receptor
(B) Enzyme linked receptor
(a) Receptor tyrosine kinase: Example- Ras MAP Kinase Pathway
 Introduction
 Components of MAP Kinase Pathway
 What is Ras?
 Process of activation of G-protein (Ras)
 Need for activation of Ras?
 Steps in Ras-MAP Kinase Pathway
 Importance of MAP Kinase Pathway
(b) Tyrosine Kinase Associated Receptor: Example- JAK-STAT Pathway
 Introduction
 Steps in JAK-STAT Pathway
 Importance of JAK-STAT Pathway
(III) Second Messengers
(IV) Transcription factors
(V) Cellular effects
Reference

3.  All cells receive and respond to signals from their environment.
 No cell lives in isolation.
 Cell signaling is a mechanism by which all the cells receive and
respond to the various signals from their surroundings.
 This is accomplished by a variety of signal molecules that are secreted
by a cell and bind to the receptors present on another cell.
 Each cell is programmed to respond to specific extracellular signal
molecules.
“Cell signaling is defined as the mechanism of communication
in which information is relayed across the plasma membrane
to the cell interior and often to the nucleus of the cell by the
means of a series of molecular interactions”.

4. EXTRACELLULAR SIGNALING INVOLVES THE
FOLLOWING STEPS:
 Synthesis and release of the
ligand by the signaling cell.

 Transport of the signal to
the target cell.

 Binding of the signal by a
specific receptor leading to
its activation.

 Initiation of the signal
transduction pathway.

5. COMPONENTS OF CELL
SIGNALING

6. LIGAND: Signal
molecules are chemically
heterogeneous
compound that bind to
other molecules.
Membrane bound: These
molecules are contact
depending ligands as they
bind to the cell surface
receptors.
Secretory signal molecules:
These cells can function by autocrine
(transmission in the same cell),
endocrine (transmission to long
distances), and paracrine
(transmission in nearby cells or short
distances) modes.
Receptors: These are
chemically protein or
glycoprotein molecules
which bind to signaling
molecule.
Intracellular receptor:
These receptors are located in
the cytosol or the nucleus. They
respond to small hydrophobic
signaling molecules that are able
to diffuse across the plasma
membrane. Examples: Steroid,
thyroid and vitamins.
Extracellular/Cell
surface receptors: These
receptors are generally found in
the plasma membrane. All
hydrophilic signaling molecules
as well as some lipophylic
molecules binds to cell surface
receptor proteins.

7. Extracellular/Cell
surface receptors
Enzyme linked
receptors
Receptor tyrosine
kinase: Example-
Ras Map Kinase
Pathway
Tyrosine Kinase
Associated Receptor:
Example- JAK-STAT
Pathway
G-protein
coupled
receptor
Cellular activator or
Second messenger:
Second messengers are
small, non-protein, water-
soluble molecules or ions
that spread throughout a
cell by diffusion. Example-
cAMP, Ca+2.
Transcription
factors: Transcription
factors are proteins that
help turn specific genes
"on" or "off" by binding to
nearby DNA. They in the
process of converting, or
transcribing, DNA into
RNA. Example- STATs,
ELK, ETS, etc.
Cellular effects:
These are the various
activities performed by
the cells for growth and
various other metabolic
processes. Example- cell
division, cell synthesis,
cell growth, etc.

8. ENZYME LINKED RECEPTORS
These are trans-membrane receptors where the binding of an extracellular
ligand causes enzymatic activity on the intracellular side.
Protein tyrosine kinase are the enzymes that phosphorylate
specific tyrosine residues on the protein substrates.
Receptor tyrosine kinase pathway (RTKs)
 The receptor tyrosine kinases (RTKs) are the largest class of cell surface
receptors.
 They may be ligand for epidermal growth factor (EGF), platelet derived
growth factor (PDGF), fibroblast growth factor (FGF).
 Most of the RTKs are monomeric, and ligand binding to the extracellular
domain which includes the formation of dimmers.
 Ligand binding leads to the activation of the intrinsic protein-tyrosine
kinase activity of the receptor and autophosphorylation of tyrosine
residues in its cytoplasmic domain.
 The activated receptor also can phosphorylate other protein substrates.
Example- GTPase activating protein (GAP).

9. RAS MAP KINASE PATHWAY/RAS-
RAF-MEK-ERK PATHWAY
Mitogen activated protein kinase (MAP) pathway refers to a cascade of
protein kinases that are highly conserved in evolution and play central roles
in signal transduction in all eukaryotic cells ranging from yeasts to humans.

10. WHAT IS RAS?
Ras is an intracellular monomeric GTPAse switch protein and functions in
transducing signals from many different RTKs (it is a lipid linked covalently
attached lipid groups) protein present at the cytoplasmic face of the membrane.
Ras proteins are present in two different forms-
1. An active GTP-bound form
2. An inactive GDP-bound
Ras-GTP binds and activates downstream signaling proteins.

12. STEPS FOR RAS ACTIVATION

13. NEED FOR ACTIVATION OF RAS?
The RAs-MAP kinase cascade is turned on in response to a wide variety of
extracellular signals and plays a key role in regulating vital activities such as cell
proliferation and differentiation.
The pathway relay the extracellular signals from the plasma
membrane through the cytoplasm and into the nucleus.
PLASMA MEMBRANE  CYTOPLASM  NUCLEUS

14. DIAGRAMMATIC REPRESENTATION

15. STEPS IN RAS-MAP KINASE PATHWAY (VISUAL VIEW)

16. FLOWCHART
Binding of the growth factor (EGF, PDGF) to its receptor leads to the
autophosphorylation of tyrosine residues of the receptor.

The subsequent recruitment of the Grb2-Sos proteins.

This complex causes the GTP-GDP exchange of Ras.

This recruits the protein Raf to the membrane, where it is phosphorylated and
thus activated.

Raf phosphorylates and activates another kinase named MEK.

MEK in turn phosphorylates and activates another kinase termed ERK.

Once activated, MAPK translocates into the nucleus where it phosphorylates
transcription factors (TF), such as Elk-1.


17. TOGETHER RAF, MEK AND ERK MAKE UP THE
THREE-TIERED KINASE PATHWAY CALLED MITOGEN
ACTIVATED PROTEIN KINASE (MAPK) CASCADE.
Phosphorylation of the transcription factors increases their affinity for regulatory sites
on the DNA.

Leads to an increase in the transcription of specific genes, Example- Fos and Jun,
involved in the growth response.

One of the genes whose expression is stimulated encodes a MAPK phosphatase (MKP-
1).

Members of the MKP family can remove phosphate groups from both tyrosine and
threonine residues of MAPK.

This inactivates MAPK and stops further signaling activity along the pathway.

18. IMPORTANCE OF MAP KINASE
PATHWAY
 In yeast, the MAP kinase cascade is required for the cells to
respond to the mating pheromones.
 In higher eukaryotes such as Drosophila, frogs and mammals
they are regulators of cell growth and differentiation.
 In fruit flies, the pathway is utilized during the differentiation
of the photoreceptors in the compound eye.
 In flowering plants, the pathway transmits signals that initiate
a defense against pathogen.
 Raf is also termed as MAPKKK, i.e., MAP Kinase Kinase
Kinase
 MEK is also termed as MAPKK, i.e., MAP Kinase Kinase
 ERK is also termed as MAPK, i.e., MAP Kinase

19. TYROSINE KINASE ASSOCIATED
RECEPTOR
 Rather than possessing intrinsic enzymatic activity, many enzyme linked receptors
act by stimulating intracellular protein tyrosine kinases with which they are non-
covalently associated.
 These enzymes associate with intracellular proteins that have tyrosine kinase
activity.
 The most largest and diverse class of tyrosine kinases associated receptors is
cytokine receptors.
 Cytokines bind to specific receptors on the target cells.
 Cytokines are low-molecular weight proteins that regulate the nature, intensity and
duration of the immune response by exerting a variety of effects on lymphocytes and
other cells.
 The cytokines utilize a novel signal transduction pathway referred to as JAK-STAT
Pathway, which operates without the involvement of a secondary messenger.
 The use of JAK-STAT Pathway transmits information from extracellular chemical
signals to the nucleus.

20.  This results in the transcription and expression of genes involved in
immunity, proliferation, differentiation, apoptosis and oncogenesis.
“JAK”Janus Kinases. It is a family of cytoplasmic tyrosine kinases
whose members become activated following the binding of a cytokine to a
cell-surface receptor.
In mammals, the JAK family comprises four members: JAK1,
JAK2, JAK 3 and Tyk2.
Janus is a two-faced Roman God who protected entrances and doorways.
“STAT”  Signal Transducers and Activators of Transcription
 In mammals, there are six types of STATs: STAT1, STAT2, STAT3,
STAT4, STAT5 and STAT6.
 JAK phosphorylate and activate gene regulatory proteins called STATS.
 STAT proteins are located in the cytosol and after activation migrate
into the nucleus and regulate gene transcription.
 Any defects in this pathway results in the immune deficiency
syndromes and cancer.

21. COMPONENTS OF JAK-STAT
PATHWAY

22. DIAGRAMMATIC REPRESENTATION

23. STEPS IN JAK-STAT PATHWAY (VISUAL PRESENTATION)

24. FLOWCHART
Cytokine bind simultaneously to the two receptor monomers.

This brings the two associated kinases (JAKs) closer together.

The associated JAKs cross phosphorylate each other and leads to the activation of JAK.

Activated JAKs than phosphorylate the specific tyrosine residues present on the intracellular
domain of the cytokine receptor.

Phosphotyrosines then serves as the “docking sites” for SH2 domain containing proteins called
STATs.

After STATs dock on, it is phosphorylated by members of the JAK family of non-receptor
protein-tyrosine kinases, which are associated with cytokine receptors.

Tyrosine phosphorylation promotes the dimerization of STAT proteins.

It is then translocated to the nucleus where they stimulate the transcription of target genes.

25. IMPORTANCE OF JAK-STAT PATHWAY
 JAK-STAT signaling pathway plays an important role in
animal development.
 The pathway can promote blood cell division, as well
as differentiation (the process of a cell becoming more
specialized).
 In some flies with faulty JAK genes, too much blood cell
division can occur, potentially resulting in leukemia.
 JAK-STAT signaling has also been associated with
excessive white blood cell division in humans and mice.
 The signaling pathway is also crucial for eye development
in the fruit fly (Drosophila melanogaster). When mutations
occur in genes coding for JAKs, some cells in the eye may be
unable to divide, and other cells, such as photoreceptor cells,
have been shown not to develop correctly.

26. ACRONYMS USED-
MAP- Motigen activate protein
GTP- Guanine triphosphate
GDP- Guanine diphosphate
GDI- Guanine nucleotide dissociation inhibitor
GEF- Guanine nucleotide exchange factor
Grb2- Growth factor receptor bound 2
Sos- Son of sevenless
Raf- Rapidly accelerated fibrosarcoma
ERK- Extracellular signal regulated kinase
JAK- Janus kinase
STAT- Signal Transducers and Activators of Transcription
EGF- Epithelial growth factor
PDGF- Platelet derived growth factor
REFERENCE:
 Cell and Molecular Biology: Gerald Karp
 The cell a molecular approach: Geofrrey M. Cooper and Rober
E. Hausma
 Pathfinder LS-Part-1