KBTBD2 (7p14.3), BKLHD1, Insuliinisignaloinnin essentielli säätelijä. Substraattina PI3KR1 p85alfa.

https://www.ncbi.nlm.nih.gov/gene/25948

Also known as

BKLHD1

Expression

Ubiquitous expression in gall bladder (RPKM 16.7), bone marrow (RPKM 14.7) and 25 other tissues See more

Preferred Names

kelch repeat and BTB domain-containing protein 2

Names

BTB and kelch domain containing 1

BTB and kelch domain-containing protein 1

kelch repeat and BTB (POZ) domain containing 2

mRNA and Protein(s)

1. NM_015483.3 → NP_056298.2  kelch repeat and BTB domain-containing protein 2
   See identical proteins and their annotated locations for NP_056298.2

   Conserved Domains (4) summary

   PHA03098
   Location:23 → 516

   PHA03098; kelch-like protein; Provisional

   sd00038
   Location:310 → 366

   Kelch; KELCH repeat [structural motif]

   cd18270
   Location:5 → 137

   BTB_POZ_KBTBD2_BKLHD1; BTB (Broad-Complex, Tramtrack and Bric a brac)/POZ (poxvirus and zinc finger) domain found in Kelch repeat and BTB domain-containing protein 2 (KBTBD2)

   cd18479
   Location:128 → 223

   BACK_KBTBD2; BACK (BTB and C-terminal Kelch) domain found in Kelch 
   repeat and BTB domain-containing protein 2 (KBTBD2)
   
   

ORIGIN      
        1 mstqderqin teyavslleq lklfyeqqlf tdivlivegt efpChkmvla tCssyframf
       61 msglseskqt HvHlrnvdaa tlqiiityay tgnlamndst veqlyetacf lqvedvlqrc
      121 reylikkina encVRLLsfa dlfsceelkq sakrmvehkf tavyhqdafm qlshdllidi
      181 lssdnlnvek eetvreaaml wleyntesrs qylssvlsqi ridalsevtq rawfqglppn
      241 dksvvvqgly ksmpkffkpr lgmtkeemmi fieassenpc slyssvcysp qaekvyklcs
      301 ppadlhkvgt vvtpdndiyi aGGqvplknt ktnhsktskl qtafrtvncf YWfdaqqntw
      361 fpktpmlfvr ikpslvcceg yiyaiGGdsv ggelnrrtve rYdtekdeWt mvsplpcawq
      421 wsaavvvhdc iyvmtlnlmy cyfprsdswv emamrqtsrs fasaaafgdk ifyiGGlhia
      481 tnsgirlpsg tvdgssvtve iYdvnkneWk maanipakry sdpcvravvi snslcvfmre
      541 thlnerakyv tyqydleldr wslrqhiser vlwdlgrdfr ctvgklypsc leespwkppt
      601 ylfstdgtee feldgemval ppv
//

LLxxL

 https://www.pnas.org/content/113/42/E6418
Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):E6418-E6426. Epub 2016 Oct 5.

Insulin resistance and diabetes caused by genetic or diet-induced KBTBD2 deficiency in mice.

Zhang Z¹, Turer E¹, Li X¹, Zhan X¹, Choi M¹, Tang M¹, Press A¹, Smith SR², Divoux A², Moresco EM¹, Beutler B³. Abstract

We describe a metabolic disorder characterized by lipodystrophy, hepatic steatosis, insulin resistance, severe diabetes, and growth retardation observed in mice carrying N-ethyl-N-nitrosourea (ENU)-induced mutations. The disorder was ascribed to a mutation of kelch repeat and BTB (POZ) domain containing 2 (Kbtbd2) and was mimicked by a CRISPR/Cas9-targeted null allele of the same gene. Kbtbd2 encodes a BTB-Kelch family substrate recognition subunit of the Cullin-3-based E3 ubiquitin ligase. KBTBD2 targeted p85α, the regulatory subunit of the phosphoinositol-3-kinase (PI3K) heterodimer, causing p85α ubiquitination and proteasome-mediated degradation. In the absence of KBTBD2, p85α accumulated to 30-fold greater levels than in wild-type adipocytes, and excessive p110-free p85α blocked the binding of p85α-p110 heterodimers to IRS1, interrupting the insulin signal. Both transplantation of wild-type adipose tissue and homozygous germ line inactivation of the p85α-encoding gene Pik3r1 rescued diabetes and hepatic steatosis phenotypes of Kbtbd2^-/- mice. Kbtbd2 was down-regulated in diet-induced obese insulin-resistant mice in a leptin-dependent manner. KBTBD2 is an essential regulator of the insulin-signaling pathway, modulating insulin sensitivity by limiting p85α abundance. KEYWORDS:

Kbtbd2;
 diabetes;
 insulin resistance;
 p85α;

GeneCards Summary for PIK3R1 Gene PIK3R1 (Phosphoinositide-3-Kinase Regulatory Subunit 1) is a Protein Coding gene. Diseases associated with PIK3R1 include Short Syndrome and Agammaglobulinemia 7, Autosomal Recessive. Among its related pathways are Gastric cancer and Interleukin-7 signaling. Gene Ontology (GO) annotations related to this gene include GTP binding and transcription factor binding. An important paralog of this gene is PIK3R2.

ubiquitination

 https://www.spandidos-publications.com/article_images/ijmm/35/2/IJMM-35-02-0305-g00.jpg
(Suom. Huomaa kuvassa insuliinisignaloinnista entsyymi PI3K, jolla on akksi alayksikköä. Toinen p85, regulatorinen alayksikkö. Tälle alayksikölle toimii KBTBD2 adaptorina  jonka avulla CLR3 ubikitiiniligaasi voi siirtää ubikitiinin p85- alayksikköön ja lähettää sen proteosomaaliseen hajoitukseen, mikä  säätää alas PI3K-aktiivisuutta.  ja täten useita metabolisia  tapahtumia. 
Vaikka KBTBD2 geenivaikutus  puuttuisi,  pelkästään tuon alayksikön PI3Kr1 inaktivaatio voisi korjata  haittoja (diabetes, maksan rasvoittuma, mitkä seuraavat  geenin KBTBD2 funktion  puuttumisesta.
Mutta  geenillä PI3KR1 on muitakin  funktioita, joita  siihen liittyneistä taudeista tunnetaan.