huntingtin-interacting protein 1; HIP-1 (HIP1)

Introduction

Expanded polyglutamine tract in huntingtin disrupts interaction between huntingtin & HIP1. Also interacts with huntingtin-interacting protein 1-related protein

Function

• role in clathrin-mediated endocytosis & trafficking
• role in regulating AMPA receptor trafficking in the central nervous system (NMDA-dependent)
• enhances androgen receptor (AR)-mediated transcription
• may act as a proapoptotic protein that induces cell death by acting through the intrinsic apoptosis pathway
• binds 3-phosphoinositides (via ENTH domain)
• may act through the ENTH domain to promote cell survival by stabilizing receptor tyrosine kinases following ligand- induced endocytosis
• may play a functional role in the cell filament networks
• may be required for differentiation, proliferation, &/or survival of somatic & germline progenitors
• binds actin
• binds HTT (via N-terminus); interaction restricted to brain
• binds to IFT57
• in normal conditions, it poorly interacts with IFT57, HIP1 being strongly associated with HTT
• in mutant HTT proteins with a long poly-Gln region, interaction between HTT & HIP1 is inhibited, promoting the interaction between HIP1 & IFT57
• interacts with CLTB (via N-terminus)
• interacts (via coiled coil domain) with AR
• interacts with AP2A1, AP2A2, CLTC & HIP1R
• interacts with GRIA1, GRIN2A & GRIN2B

Structure

• homodimer
• pseudo DED region (pDED) mediates interaction with IFT57
• binds F-actin via the talin-like I/LWEQ domain
• belongs to the SLA2 family
• contains 1 ENTH (epsin N-terminal homology) domain
• contains 1 I/LWEQ domain

Compartment

• cytoplasm, nucleus, endomembrane system
• cytoplasmic vesicle, clathrin-coated vesicle membrane
• shuttles between cytoplasm & nucleus
• nuclear translocation can be induced by AR

Alternative splicing

named isoforms=2; HIP1-1, HIP1-2

Expression

• ubiquitously expressed with the highest level in brain
• expression is up-regulated in prostate & colon cancer

Pathology

• chromosomal translocation t(5;7)(q33;q11.2) involving HIP1 with PDGFRB is found in a form of chronic myelomonocytic leukemia (CMML)
• the chimeric HIP1-PDGFRB transcript results from an in-frame fusion of the two genes
• the reciprocal PDGFRB-HIP1 transcript is not expressed
• the affinity of the huntingtin protein-HIP1 interaction is inversely correlated to the length of the polyglutamine tract added to the huntingtin protein in Huntington disease

More general terms

• phosphoprotein

Additional terms

• histone-lysine N-methyltransferase SETD2 (SET domain-containing protein 2, hSET2, Huntingtin-interacting protein HYPB, Huntingtin yeast partner B, Huntingtin-interacting protein 1, HIF-1, p231HBP, SETD2, HIF1, HYPB, KIAA1732, SET2, HSPC069)
• huntingtin-interacting protein 1-related protein; HIP1-related protein; huntingtin-interacting protein 12; HIP-12 (HIP1R, HIP12, KIAA0655)
• Huntington's disease [HD] protein (huntingtin) or IT15 protein

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=3092
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:3092
• OMIM: https://mirror.omim.org/entry/601767
• UniProt: http://www.uniprot.org/uniprot/O00291.html