SIAH1

This gene encodes a protein that is a member of the seven in absentia homolog (SIAH) family. The protein is an E3 ligase and is involved in ubiquitination and proteasome-mediated degradation of specific proteins. The activity of this ubiquitin ligase has been implicated in the development of certain forms of Parkinson's disease, the regulation of the cellular response to hypoxia and induction of apoptosis. Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized. [provided by RefSeq]

seven in absentia homolog 1 (Drosophila)

E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:14506261, PubMed:14645235, PubMed:14654780, PubMed:15064394, PubMed:16085652, PubMed:19224863, PubMed:20508617, PubMed:22483617, PubMed:9334332, PubMed:9858595, PubMed:28546513, PubMed:32430360, PubMed:33591310).
E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates (PubMed:14506261, PubMed:14645235, PubMed:14654780, PubMed:15064394, PubMed:16085652, PubMed:19224863, PubMed:20508617, PubMed:22483617, PubMed:9334332, PubMed:9858595).
Mediates E3 ubiquitin ligase activity either through direct binding to substrates or by functioning as the essential RING domain subunit of larger E3 complexes (PubMed:14506261, PubMed:14645235, PubMed:14654780, PubMed:15064394, PubMed:16085652, PubMed:19224863, PubMed:20508617, PubMed:22483617, PubMed:9334332, PubMed:9858595).
Triggers the ubiquitin-mediated degradation of many substrates, including proteins involved in transcription regulation (ELL2, MYB, POU2AF1, PML and RBBP8), a cell surface receptor (DCC), the cell-surface receptor-type tyrosine kinase FLT3, the cytoplasmic signal transduction molecules (KLF10/TIEG1 and NUMB), an antiapoptotic protein (BAG1), a microtubule motor protein (KIF22), a protein involved in synaptic vesicle function in neurons (SYP), a structural protein (CTNNB1) and SNCAIP (PubMed:10747903, PubMed:11146551, PubMed:11389839, PubMed:11389840, PubMed:11483517, PubMed:11483518, PubMed:11752454, PubMed:12072443).
Confers constitutive instability to HIPK2 through proteasomal degradation (PubMed:18536714, PubMed:33591310).
It is thereby involved in many cellular processes such as apoptosis, tumor suppression, cell cycle, axon guidance, transcription regulation, spermatogenesis and TNF-alpha signaling (PubMed:14506261, PubMed:14645235, PubMed:14654780, PubMed:15064394, PubMed:16085652, PubMed:19224863, PubMed:20508617, PubMed:22483617, PubMed:9334332, PubMed:9858595).
Has some overlapping function with SIAH2 (PubMed:14506261, PubMed:14645235, PubMed:14654780, PubMed:15064394, PubMed:16085652, PubMed:19224863, PubMed:20508617, PubMed:22483617, PubMed:9334332, PubMed:9858595).
Induces apoptosis in cooperation with PEG3 (By similarity).
Upon nitric oxid (NO) generation that follows apoptotic stimulation, interacts with S-nitrosylated GAPDH, mediating the translocation of GAPDH to the nucleus (By similarity).
GAPDH acts as a stabilizer of SIAH1, facilitating the degradation of nuclear proteins (By similarity).
Mediates ubiquitination and degradation of EGLN2 and EGLN3 in response to the unfolded protein response (UPR), leading to their degradation and subsequent stabilization of ATF4 (By similarity).
Also part of the Wnt signaling pathway in which it mediates the Wnt-induced ubiquitin-mediated proteasomal degradation of AXIN1 (PubMed:28546513, PubMed:32430360).

Biological Process amyloid fibril formationTAS:Reactome
Biological Process anatomical structure morphogenesisManual Assertion Based On ExperimentTAS:ProtInc
Biological Process apoptotic processManual Assertion Based On ExperimentTAS:ProtInc
Biological Process axon guidanceManual Assertion Based On ExperimentTAS:ProtInc
Biological Process canonical Wnt signaling pathwayManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process cell cycleIEA:UniProtKB-KW
Biological Process nervous system developmentManual Assertion Based On ExperimentTAS:ProtInc
Biological Process neuron apoptotic processISS:UniProtKB
Biological Process positive regulation of apoptotic processManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of intrinsic apoptotic signaling pathwayManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process proteasome-mediated ubiquitin-dependent protein catabolic processManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process protein catabolic processManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process spermatogenesisIEA:UniProtKB-KW
Biological Process ubiquitin-dependent protein catabolic processManual Assertion Based On ExperimentIDA:MGI

Cytoplasm
Nucleus
Predominantly cytoplasmic. Partially nuclear.

Buratti-Harel syndrome (BURHAS):
An autosomal dominant neurodevelopmental disorder characterized by hypotonia apparent in early infancy, global developmental delay, delayed walking, language and speech delay, impaired intellectual development, and dysmorphic facial features.

Phosphorylated on Ser-19 by ATM and ATR. This phosphorylation disrupts SIAH1 interaction with HIPK2, and subsequent proteasomal degradation of HIPK2.