Insulin signaling system

Pathways: [Papers] [Insulin Signaling] [IGF Signaling] [ BLAST results for ins signaling components ] [ 100 genes in the window ]

Papers

Mitogen activated protein kinase pathways mediated by ERK, JNK and p38 protein kinases

Insulin signaling pathway

Insulin signaling pathway is conserved across species. The figure ( Garofalo, TIEM 2002, pdf) below shows the conserved pathways in fly, worm and mammals. Although, it is not clear whether the insulin signaling is different from the IGF signaling, this figure treats them as the same.

This notes briefly discusses the conserved components of insulin signaling systems in fly and human. The conserved components were identified by literature search.

Fly Human Ensembl IDs

DILP Insulin -

DINR Insulin Receptor -

CHICO Insulin Receptor Substrate(IRS) IRS1: ENSG00000169047, IRS2: ENSG00000185950 IRS3, IRS4: ENSG00000133124

P60 P85alpha, P85beta and P85gamma P85alpha : ENSG00000145675 , P85beta : ENSG00000105647 , P85gamma :ENSG00000117461

DP110 P110alpha P110alpha: ENSG00000121879, P110beta: ENSG00000051382, P110delta: ENSG00000171608

DPDK1 PDK1 -

DPTEN PTEN -

DAKT AKT -

DS6K P70S6K -

DILP and Insulin

DILP is an acronym of (Drosphila Insulin-Like Peptide). In drosophila genome, seven DILPs have identified based on sequence homology. DILP1-7 are structurally similar to preproinsulin, with a predicted signal peptide, B chain, C peptide, and A chain.

DINR and Insulin receptor

DINR stands for Drosophila Insulin Receptor.

CHICO and IRS

CHICO is an adaptor protein and it binds to DINR. CHICO is a protein of 968 residues long. It contains an N-terminal PH domain, PTB domain , and a C-terminal region containing multiple potential tyrosine phosphorylation sites. The PTB domain binds to phosphotyrosine residues in INR , whereas phosphorylated C-terminal tyrosine residues within the consensus Tyr-X-X-Met are thought to bind to the Drosophila class Ia phosphoinositide 3-kinase adaptor, p60.

CHICO is the Drosophila homolog of mammalian Insulin Receptor Substrate (IRS) proteins( PH domain and PTB domain (IRS-1 type) ). Although, there are four IRS proteins in human genome, only IRS1 and IRS2 are known to play role in insulin signaling. ( IRS1 - Chr 2, IRS2 - Chr 13, IRS3 - Chr 12 and IRS4 - Chr X).

P60 and P85 gamma

P60 in fly is an SH2 domain-containing adaptor molecule that binds to the Drosophila class Ia phosphoinositide 3 kinase, Dp110. p60 shares sequence homology with mammalian p85alpha, p85beta, and p55PIK. p60 contains two SH2 domains that recognize phosphorylated tyrosine residues within the consensus Tyr-X-X-Met, and an inter-SH2 domain region through which it interacts with Dp110.

The mammalian homologs of P60 are P85alpha (Chr 5), P85beta (Chr 19) and P85gamma (Chr 1). The full names of these human proteins are Phosphatidylinositol 3-kinase regulatory alpha/beta/gamma subunit (PI3-kinase p85-alpha/beta/gamma subunit) (PtdIns-3-kinasep85-alpha/beta/gamma). The STKE connection map lists p85gamma in the insulin signaling pathway. I need find out the roles of P85alpha and P85beta.

DP110 and P110alpha

Dp110 is the Drosophila class Ia phosphoinositide 3-kinase and contains an N-terminal domain predicted to bind to the SH2 domain-containing adaptor molecule, p60, a Ras-binding domain, a C2 domain, an alpha-helical PIK domain and a catalytic domain. Dp110 possesses phosphoinositide 3-kinase activity and, in vitro, can phosphorylate PI to generate PI(3)P, PI(4)P to generate PI(3,4)P2, and PI(4,5)P2 to generate PI(3,4,5)P3. By analogy with mammalian class Ia phosphoinositide 3-kinases, PI(3,4,5)P3 is thought to be the major product of Dp110 in vivo. Mammalian homologs of Dp110 are p110alpha, p110 beta, p110delta.

The p110 catalytic subunits of class Ia phosphoinositide 3-kinases (PI3Ks) form stable heterodimeric complexes with p85 family regulatory subunits. These proteins all have N-terminal regions that mediate binding to the regulatory subunit, followed by a Ras binding domain, a C2 domain, an alpha-helical phosphoinositide kinase domain, and a catalytic domain. p110 Class Ia phosphoinositide 3-kinase catalytic subunits have the following components:

p110alpha catalytic subunit of phosphoinositide 3-kinase (p110alpha)

p110beta catalytic subunit of phosphoinositide 3-kinase (p110beta)

p110delta catalytic subunit of phosphoinositide 3-kinase (p110delta)

There are four other p110 molecules in human with domain architectures identical to the above p110 subunits. I need to look up their functions and their roles in insulin/IGF signaling.

DPDK1 and PDK1

Drosophila phosphoinositide-dependent kinase 1 contains and N-terminal serine/threonine kinase domain and C-terminal PH domain. It seems that human genome has only one PDK1.

DPTEN and PTEN

DPTEN suppresses class Ia phosphoinositide 3-kinase signaling by removing the D3 phosphate group from PI(3)P, PI(3,4)P2, PI(3,4,5)P3. DPTEN has a protein tyrosine phosphatase domain at its N termimus.

The mammalian homolog of DPTEN is PTEN. PTEN stands for phosphatase and tension homolog. PTEN also has a Protein tyrosine phosphatase domain. Human genome has two PTEN genes, one in Chr 9 and the other in Chr 10.

DAKT and AKT1

Dakt is a serine/threonine kinase, involved in positive regulation of cell size. AKT is the mammalian homolog of Dakt. AKT is also known as protein kinase B(PKB). There are three AKTs: AKT1 (Chr 14), AKT2 (Chr 19) and AKT3(Chr 1) in the human genome.