The document summarizes the MAPK (mitogen-activated protein kinase) signaling cascade downstream of insulin receptor activation. It discusses: 1) Upon insulin binding, the insulin receptor phosphorylates IRS-1, which recruits Grb2 and Sos to activate Ras. 2) Ras activates the Raf kinase, which phosphorylates and activates the MEK kinase. 3) MEK then phosphorylates and activates ERK, a MAP kinase that translocates to the nucleus. 4) Nuclear ERK phosphorylates transcription factors like Elk1, stimulating gene transcription required for cell division.

1. MAPK Cascade<br />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.<br />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.<br />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.<br />MAPK was originally called quot;
extracellular signal-regulated kinasesquot;
(ERKs) and quot;
microtubule-associated protein kinasequot;
(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.<br />Insulin receptor binds insulin and undergoes autophosphorylation on its carboxyl-terminal Tyr residues.<br />Insulin receptor phosphorylates IRS-1 on its Tyr residues.<br />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.<br />Activated Ras binds and activates Raf-1<br />Raf-1 phosphorylates MEK on two Ser residues, activating it. MEK phosphorylates ERK on a Thr and a Tyr residue, activating it<br />ERK moves into the nucleus and phosphorylates nuclear transcription factors such as Elk1<br /> All these steps occurs in Cytosol<br />Phosphorylated Elk1 joins SRF to stimulate the transcription and translation of a set of genes needed for cell division(In Nucleus)<br />Fig: MAPK cascades<br />Growth factors, cytokines<br /> MAPK cascade<br />Phosphorylation of Jun and Fos in nucleus<br /> <br /> Cyclins,CDKs Transcription FactorE2F <br /> Transcriptional regulation<br />Enzymes for DNA synthesis<br /> Passage from G1 to S phase<br />Fig: Regulation of cell division by growth factors.<br />Protein NamePathway SectionsNo. of InteractionsAREGLigand2ARRB1Co-Factor8ATF 1Transcription Factor3ATF 2Transcription Factor2AXINMediator15BRAFMediator5BTCLigand2CBLE3Co-Factor2CDC42Mediator5CNK1Co-factor1CNK2Co-factor1CREB1Transcription FactorCo-factor7CRIPAKCo-factor1CRKCo-factor1DAXXMediatorCo-factor3DDIT3Transcription Factor1DUSP16Co-factor2DUSP19Co-factor1DUSP22Co-factor1DVL3Mediator8EGFLigand2EGFRReceptor15EIF4ECo-factorOther4ELK1Transcription Factor3ELK3Transcription Factor3ELK4Transcription Factor2ERK1Mediator32ERK2Mediator21ERK5Mediator4ETS 1Transcription factor1ErbB2Receptor7ErbB3Receptor4ErbB4Receptor8FLNACoFactor1FOSTranscription Factor3FYNOther1GAB1Mediator8GRB2MediatorGSK3BMediatorCo Factor22HBEGFLigand2HVH-3Co-Factor2HVH-5Co-Factor2IGF-1RReceptor14IKBKAPCoFactor1IRAK 1Medator3IRS 1Mediator10IRS 4Co-Factor5JAK 1Mediator37JIP-1CoFactor9JIP-2CoFactor6JIP-3CoFactor7JIP-4CoFactor4JNK 1Mediator21JNK 2Mediator4JNK 3Mediator4JNKK1Mediator22JNKK2Mediator14JUNTranscription Factor5KAPCAMediator9KSR 1Co-factor2KSR 2Co-Factor1LRIG1Mediator5MAPK310 MLK2Mediator4MAP3K11 SPRKMediator7MAP3K12 ZPKMediator5MAP3K13 LZKMediator2MAP3K16 TAO1MediatorCo-factor1MAP3K17 TAO2Mediator4MAP3K18 TAO3Co-factor1MAP3K7IP1 TAB1Co-Factor5MAP3K7IP2 TAB2Co-Factor3<br />Fig: Signaling proteins in the EGF/MAPK pathway of H. sapiens<br />