growth factor receptor-bound protein 10; GRB10 adapter protein; insulin receptor-binding protein Grb-IR (GRB10 GRBIR KIAA0207)

Function

• adapter protein that modulates coupling of cell surface receptor tyrosube kinases with specific signaling pathways
• binds to, & suppress signals from, activated receptor tyrosine kinases, including the insulin receptor (INSR) & insulin-like growth factor receptor (IGF1R)
• the inhibitory effect can be achieved by 2 mechanisms:
  • interference with the signaling pathway
  • increased receptor degradation
• interacts via SH2 domain with cytoplasmic domain of autophosphorylated insulin receptor, inhibits it
• delays & reduces AKT1 phosphorylation in response to insulin stimulation
• blocks association between INSR & IRS1 & IRS2 & prevents insulin-stimulated IRS1 & IRS2 Tyr phosphorylation
• recruits NEDD4 to IGF1R, leading to IGF1R ubiquitination, increased internalization & degradation by both the proteasomal & lysosomal pathways
• may play a role in mediating insulin-stimulated ubiquitination of INSR, leading to proteasomal degradation
• negatively regulates Wnt signaling by interacting with LRP6 intracellular portion & interfering with the binding of AXIN1 to LRP6
• positive regulator of the KDR/VEGFR-2 signaling pathway
• may inhibit NEDD4-mediated degradation of KDR/VEGFR-2 phosphorylated on Ser upon EGF, FGF & PDGF stimulation (putative)
• interacts with ligand-activated tyrosine kinase receptors, including FGFR1, INSR, IGF1R, MET & PDGFRB phospho-Tyr- dependent) through the SH2 domain
• poorly binds to the EGFR (putative)
• directly interacts with MAP3K14/NIK & is recruited to the EGFR-ERBB2 complex. interacts with GIGYF1/PERQ1 & GIGYF2/TNRC15
• when unphosphorylated, interacts with AKT1
• when phosphorylated, interacts with YWHAE (14-3-3 epsilon)
• interacts with NEDD4
• interacts with LRP6, thus interfering with the binding of AXIN1 to LRP6 (putative)
• binds to activated NRAS

Structure

• PH domain binds relatively non-specifically to several phosphoinositides, including PI(5)P, PI(4,5)P2, PI(3,4)P2 & PI(3,4,5)P3, with modest affinities
• belongs to the GRB7/10/14 family
• contains 1 PH domain
• contains 1 Ras-associating domain
• contains 1 SH2 domain

Compartment

• cytoplasm (putative)
• when complexed with NEDD4 & IGF1R, follows IGF1R internalization, remaining associated with early endosomes
• uncouples from IGF1R-containing endosomes before the sorting of the receptor to the lysosomal compartment (putative)

Alternative splicing

named isoforms=4

Expression

• widely expressed in fetal & adult tissues, including fetal & postnatal liver, lung, kidney, skeletal muscle, heart, spleen, skin & brain
• highly expressed in skeletal muscle
• the GRB10 locus is imprinted
• during embryonic development, the expression in the brain & spinal cord is from the paternal allele, while in placental villous trophoblasts & skeletal muscle, it is from the maternal one
• expression is biallelic in most other tissues
• paternal expression in the brain is maintained throughout adulthood
• imprinting often is isoform- specific

Pathology

• GRB10 is unlikely to be responsible for Silver-Russell syndrome (SRS)

More general terms

• growth factor receptor-bound protein (GRB GRB adapter protein)
• phosphoprotein

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=2887
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:2887
• OMIM: https://mirror.omim.org/entry/601523
• UniProt: http://www.uniprot.org/uniprot/Q13322.html