Mapk cascade

Signal Pathway

1. MAPK Cascade
Insulin regulates both metabolism and gene expression: the insulin signal passes from the plasma
membrane receptor to insulin-sensitive metabolic enzymes and to the nucleus, where it stimulates
the transcription of specific genes. The α chains contain the insulin binding domain, and the
intracellular domains of the β chains contain the protein kinase activity that transfers a phosphoryl
group from ATP to the hydroxyl group of Tyr residues in specific target proteins.
One of the target protein is insulin receptor substrate-1 (IRS-1).Once phosphorylated on its Tyr
residue,messages are carried from insulin receptor to end products through intermediary
proteins.SHP domain of Grb2 protein is bound to the phosphorylated residue of IRS 1.Grb2 another
domain SH3 binds to the proline rich region of Sos.GDP of Ras (a G protein ) is replaced by GTP by
Grb2 bound SH3.Ras bound GTP activates Raf-1(first of the three protein kinases Raf-1,MEK,ERK).
The protein kinase ERK is activated by phosphorylation of both a Thr and a Tyr residue.
ERK is a member of the MAPK family (mitogen-activated protein kinases; mitogens are signals that
act from outside the cell to induce mitosis and cell division). MAP kinase kinase (MEK belongs to this
family) activates ERK. MAP kinase kinase kinase (Raf-1 is a member of this family) further activates
MAP kinase kinase. MAPK cascades is thus a series of phosphoryrlation of one protein kinase by
another.
MAPK was originally called "extracellular signal-regulated kinases" (ERKs) and "microtubule-
associated protein kinase" (MAPK). One of the first proteins known to be phosphorylated by ERK was
a microtubule-associated protein (MAP). The series of kinases from RAF to MEK to MAPK is an
example of a protein kinase cascade. Such series of kinases provide opportunities for feedback
regulation and signal amplification.

Insulin receptor binds insulin and undergoes autophosphorylation on its carboxyl-terminal Tyr
residues.

Insulin receptor phosphorylates IRS-1 on its Tyr residues.

SH2 domain of Grb2 binds to P –Tyr of IRS-1. Sos binds to Grb2, then to Ras, causing GDP release
andGTP binding to Ras.

Activated Ras binds and activates Raf-1

Raf-1 phosphorylates MEK on two Ser residues, activating it. MEK phosphorylates ERK on a Thr and
a Tyr residue, activating it

2. ERK moves into the nucleus and phosphorylates nuclear transcription factors such as Elk1
All these steps occurs in Cytosol

Phosphorylated Elk1 joins SRF to stimulate the transcription and translation of a set of genes needed
for cell division(In Nucleus)

Fig: MAPK cascades

Growth factors, cytokines

MAPK cascade

Phosphorylation of Jun and Fos in nucleus


Cyclins,CDKs Transcription FactorE2F
Transcriptional regulation

Enzymes for DNA synthesis

3. Passage from G1 to S phase
Fig: Regulation of cell division by growth factors.







Protein Name Pathway Sections No. of Interactions
AREG Ligand 2
ARRB1 Co-Factor 8
ATF 1 Transcription Factor 3
ATF 2 Transcription Factor 2
AXIN Mediator 15
BRAF Mediator 5
BTC Ligand 2
CBLE3 Co-Factor 2
CDC42 Mediator 5
CNK1 Co-factor 1
CNK2 Co-factor 1
CREB1 Transcription Factor
Co-factor
7
CRIPAK Co-factor 1
CRK Co-factor 1
DAXX Mediator
Co-factor
3
DDIT3 Transcription Factor 1
DUSP16 Co-factor 2
DUSP19 Co-factor 1
DUSP22 Co-factor 1
DVL3 Mediator 8
EGF Ligand 2
EGFR Receptor 15
EIF4E Co-factor
Other
4
ELK1 Transcription Factor 3
ELK3 Transcription Factor 3
ELK4 Transcription Factor 2
ERK1 Mediator 32
ERK2 Mediator 21
ERK5 Mediator 4

4. ETS 1 Transcription factor 1
ErbB2 Receptor 7
ErbB3 Receptor 4
ErbB4 Receptor 8
FLNA CoFactor 1
FOS Transcription Factor 3
FYN Other 1
GAB1 Mediator 8
GRB2 Mediator
GSK3B Mediator
Co Factor
22
HBEGF Ligand 2
HVH-3 Co-Factor 2
HVH-5 Co-Factor 2
IGF-1R Receptor 14
IKBKAP CoFactor 1
IRAK 1 Medator 3
IRS 1 Mediator 10
IRS 4 Co-Factor 5
JAK 1 Mediator 37
JIP-1 CoFactor 9
JIP-2 CoFactor 6
JIP-3 CoFactor 7
JIP-4 CoFactor 4
JNK 1 Mediator 21
JNK 2 Mediator 4
JNK 3 Mediator 4
JNKK1 Mediator 22
JNKK2 Mediator 14
JUN Transcription Factor 5
KAPCA Mediator 9
KSR 1 Co-factor 2
KSR 2 Co-Factor 1
LRIG1 Mediator 5
MAPK310 MLK2 Mediator 4
MAP3K11 SPRK Mediator 7
MAP3K12 ZPK Mediator 5
MAP3K13 LZK Mediator 2
MAP3K16 TAO1 Mediator
Co-factor
1
MAP3K17 TAO2 Mediator

4
MAP3K18 TAO3 Co-factor 1
MAP3K7IP1 TAB1 Co-Factor 5
MAP3K7IP2 TAB2 Co-Factor 3

Fig: Signaling proteins in the EGF/MAPK pathway of H. sapiens