Defective RB1 does not form a complex with SKP2 and FZR1

Stable Identifier
R-HSA-9687377
Type
Reaction [transition]
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
General
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

A tripartite complex formed between RB1, SKP2 and FZR1 (Cdh1) targets SKP2 for the anaphase promoting complex/cyclosome (APC/C:Cdh1)-mediated ubiquitination and subsequent proteasome-mediated degradation. Both SKP2 and FZR1 interact with the pocket domain of RB1, with amino acid residues 637–738 and 772–824 involved in SKP2 binding and the cleft region (amino acids 753–761), containing the LxCxE motif, involved in FZR1 binding (Binne et al. 2007). RB1 T738_R775del (RB1 Ex22del) cancer mutant, which lacks exon 22, is able to associate with SKP2 but unable to bind FZR1. This mutant is defective in inducing accumulation of CDKN1B (p27Kip1) and promoting mitotic exit as it cannot prevent SKP2-mediated ubiquitination and degradation of CDKN1B (Ji et al. 2004, Binne et al. 2007). RB1 T738_R775del mutant is also defective in E2F binding (Ji et al. 2004). RB1 missense mutant, RB1 R661W, which causes low penetrance familial retinoblastoma, is unable to bind to E2Fs but retains the ability to bind to SKP2 and FZR2 and to induce CDKN1B accumulation (Ji et al. 2004, Binne et al. 2007).

Literature References
PubMed ID Title Journal Year
17187060 Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit

Binné, UK, Classon, MK, Dick, FA, Wei, W, Rape, M, Kaelin, WG, Näär, AM, Dyson, NJ

Nat. Cell Biol. 2007
15469821 An Rb-Skp2-p27 pathway mediates acute cell cycle inhibition by Rb and is retained in a partial-penetrance Rb mutant

Ji, P, Jiang, H, Rekhtman, K, Bloom, J, Ichetovkin, M, Pagano, M, Zhu, L

Mol. Cell 2004
Participants
Participant Of
Normal reaction
Disease
Name Identifier Synonyms
cancer 162 malignant tumor, malignant neoplasm, primary cancer
Authored
Reviewed
Created
Cite Us!