Kelch-like protein 12

Definition:

Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a negative regulator of Wnt signaling pathway and ER-Golgi transport. The BCR(KLHL12) complex is involved in ER-Golgi transport by regulating the size of COPII coats, thereby playing a key role in collagen export, which is required for embryonic stem (ES) cells division: BCR(KLHL12) acts by mediating monoubiquitination of SEC31 (SEC31A or SEC31B). The BCR(KLHL12) complex is also involved in neural crest specification: in response to cytosolic calcium increase, interacts with the heterodimer formed with PEF1 and PDCD6/ALG-2, leading to bridge together the BCR(KLHL12) complex and SEC31 (SEC31A or SEC31B), promoting monoubiquitination of SEC31 and subsequent collagen export. As part of the BCR(KLHL12) complex, also acts as a negative regulator of the Wnt signaling pathway by mediating ubiquitination and subsequent proteolysis of DVL3. The BCR(KLHL12) complex also mediates polyubiquitination of DRD4 and PEF1, without leading to degradation of these proteins.

References:

[1]. Lingyan Jin, et al. Ubiquitin-dependent regulation of COPII coat size and function. Nature. 2012 Feb 22;482(7386):495-500. [Content Brief]

[2]. Colleen A McGourty, et al. Regulation of the CUL3 Ubiquitin Ligase by a Calcium-Dependent Co-adaptor. Cell. 2016 Oct 6;167(2):525-538.e14. [Content Brief]

[3]. Daniel C Scott, et al. Two Distinct Types of E3 Ligases Work in Unison to Regulate Substrate Ubiquitylation. Cell. 2016 Aug 25;166(5):1198-1214.e24. [Content Brief]

[4]. Pieter Rondou, et al. BTB Protein KLHL12 targets the dopamine D4 receptor for ubiquitination by a Cul3-based E3 ligase. J Biol Chem. 2008 Apr 25;283(17):11083-96. [Content Brief]

[5]. Pieter Rondou, et al. KLHL12-mediated ubiquitination of the dopamine D4 receptor does not target the receptor for degradation. Cell Signal. 2010 Jun;22(6):900-13. [Content Brief]

[6]. Stephane Angers, et al. The KLHL12-Cullin-3 ubiquitin ligase negatively regulates the Wnt-beta-catenin pathway by targeting Dishevelled for degradation. Nat Cell Biol. 2006 Apr;8(4):348-57. [Content Brief]

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