The ubiquitin ligase Siah2 and the hypoxia response

Abstract

Growing evidence indicates that ubiquitin ligases play a critical role in the hypoxia response. Among them, Siah2, a RING finger ligase, is an important regulator of pathways activated under hypoxia. Siah2 regulates prolyl hydroxylases PHD3 and 1 under oxygen concentration of 2% to 5%, thereby allowing accumulation of hypoxia-inducible factor (HIF)-1alpha, a master regulator of the hypoxia response within the range of physiological normoxic to mild hypoxic conditions. Growing evidence also indicates an important function for Siah2 in tumor development and progression based on pancreatic cancer, mammary tumor, and melanoma mouse models. This review summarizes our current understanding of Siah2 regulation and function with emphasis on hypoxia and tumorigenesis.

FIGURE 1

Hypoxic signaling connected to Siah. Under the hypoxia condition, hypoxia-activated p38 and Akt pathways positively regulate Siah2 activity through phosphorylation and induction, respectively. Siah2 is phosphorylated by p38 on its serine and threonine residues, which will enhance its activity. Akt pathway increases the abundance of Siah2 by induction of its mRNA through signaling pathways yet to be clarified. Induced and activated Siah2 modulates the hypoxic signaling through PHD3 degradation and HIF-1α stabilization on one hand. Although, it is not yet identified, other Siah2 substrates would also play roles on hypoxic signaling by both HIF-1α-dependent and -independent mechanism.

FIGURE 2

Regulation of HIF-dependent and -independent pathways by Siah2 on tumorigenesis and metastasis. Siah2 regulates the tumor growth stage by degradation of SPRY2 and subsequent activation of the Ras-ERK pathway, which is HIF-independent. Metastatic stage is also regulated by Siah2 through its effect on the PHD3-HIF pathway, which involves the growth or angiogenic ability of metastatic cells as well as maintaining their viability.

FIGURE 3

Interaction of Siah2 and Substrates. A. Siah2 substrates including PHD3 interact with SBD of Siah2, become ubiquitinated, and are subsequently degraded. PHYL peptide derived from adaptor protein phyllopod masks the SBD to interfere with the binding of the substrates, therefore serving as an inhibitor of Siah. SPRY2 is an exceptional case whose degradation is not affected by PHYL peptide, suggesting that it binds the region outside of SBD or uses some intermediate protein that has higher affinity to Siah2 than PHYL. These two different modes of interaction enable Siah2 to play different roles during tumorigenesis and metastasis. B. Alignment of Siah2 amino acid sequences among the species. Mus musculus (Siah2), Rattus norvegicus (Siah2), Homo sapiens (Siah2), Xenopus laevis (Siah2), Danio rerio(Siah2-like), Drosophila melanogaster (Sina), and Caenorhabditis elegans (Siah) sequences are compared. Completely identical amino acid residues throughout the species are boxed in black, and the residues with at least five matches out of seven are boxed in gray. Alignment was done by Clustal W program (http://clustalw.ddbj.nig.ac.jp/top-e.html).