Low penetrance germline RB1 mutants RB1 N480del and RB1 R661W, reported in retinoblastoma, localize to the nucleus but have >95% reduced binding to E2F1. These two mutations lie in the pocket region of RB1, N480del in the pocket domain A (amino acid residues 373 579) and R661W in the pocket domain B (amino acid residues 640 771). Binding of RB1 N480del and RB1 R661W to E2F2 and E2F3 has not been tested but is assumed to be affected like E2F1 binding (Otterson et al. 1997). RB1 T738_R775del mutant (also known as RB1 delEx22) is a cancer mutant that is generated by an in-frame deletion or by a splice site mutation, which both result in a mutant protein that lacks the amino acid sequence encoded by exon 22 of the RB1 gene. This mutant lacks a part of the pocket domain B and is unable to bind to the adenoviral oncoprotein E1A (Templeton et al. 1991). RB1 T738_R775del is not able to inhibit E2F1-mediate transcriptional transactivation (Helin et al. 1993) and is unable to bind to E2Fs (Ji et al. 2004).
RB1 R661Q mutant has been reported in cancer and is predicted to be pathogenic, but has not been functionally tested; it is annotated as a candidate based on its similarity with RB1 R661W.
RB1 C706F mutant, reported in lung and breast cancer, maps to the pocket domain B and shows a complete loss of binding to E2F1 (Otterson et al. 1997). Based on its similarity with RB1 C706F, RB1 C706Y mutant, reported in lung cancer, has been annotated as a candidate.
Another in-frame deletion mutant of RB1, RB1 I703_E737del (also known as RB1 delEx21) has been reported in several different cancer types. This mutant is generated by an in-frame deletion of exon 21 and is assumed to have impaired binding to E2Fs, due to its partially deleted pocket domain B. RB1 I703_E737del is annotated as a candidate for impaired binding to E2F1, E2F2 and E2F3.

MAPK1 (also known as ERK2) translocates to the nucleus in response to estrogen stimulation several cell lines in a manner that also depends on SRC, PI3K and PRCKZ (Castoria et al, 2004). RAS signaling and ERK2 nuclear translocation promotes estrogen-dependent stimulation of cell cycle progression (Castoria et al, 1999; Castoria et al, 2001; Migliaccio et al, 1996; Castoria et al, 2004; Rodier et al, 2002; Foster et al, 2003;reviewed in Castoria et al, 2010).

The COP9 signalosome (also known as CSN) is a highly conserved multi-subunit enzymatic complex that plays a role as the sole CRL ubiquitin ligase deneddylase. Deneddylation decreases ubiquitin ligase activity of CRL complexes, and is required for the subsequent binding of CAND1 to the cullin subunit. The CSN is required for stabilization of CRL substrate receptors: without the CSN, CRL complexes are "hyper-active" and promote their own degradation through autoubiquitination. Both the CSN and CAND1 allow remodeling of the ubiquitin ligase complex through exchange of the ubiquitin substrate specific receptors (Cope et al, 2006; Denti et al, 2006; Peth et al, 2007; Schmidt et al, 2009; Enchev et al, 2012; Pierce et al, 2013; Zemla et al, 2013; Wu et al, 2013, reviewed in Wei et al, 2008). Deregulation of the CRL-CSN pathway causes misregulation of numerous important cellular targets and has been implicated in the development of some cancers (reviewed in Gummlich et al, 2013).

WNT Inhibitory factor 1 (WIF1) is a secreted antagonist of WNT signaling that acts by binding to WNTs in the extracellular space and inhibiting their interaction with the FZD receptor complex (Hsieh et al, 1999; Surmann-Schmitt et al, 2009; Malinauskas et al, 2011; Banyai et al, 2012). WIF1 consists of a WIF domain (WD; also present in RYK receptors) and 5 EGF domains (Patthy 2000; Hsieh et al, 1999). Functional studies show that the WD contributes most of the WNT-binding activity while the EGF repeats make contact with components of the extracellular matrix such as HSPGs and glypicans (Hsieh et al, 1999; Malinauskas et al, 2011; Sanchez-Hernandez et al, 2012). WIF1 is downregulated in some cancers, and overexpression of human WIF1 has been shown to inhibit growth of lung and bladder cancer cells (Mazieres et al, 2004; Kansara et al, 2009; Lin et al, 2006; Tang et al, 2009)

The COP9 signalosome (also known as CSN) is a highly conserved multi-subunit enzymatic complex that plays a role as the sole CRL ubiquitin ligase deneddylase. Deneddylation decreases ubiquitin ligase activity of CRL complexes, and is required for the sCAND1 binding to the cullin subunit. The CSN is required for stabilization of CRL substrate receptors: without the CSN, CRL complexes are "hyper-active" and promote their own degradation through autoubiquitination. Both the CSN and CAND1 allow remodeling of the ubiquitin ligase complex through exchange of the ubiquitin substrate specific receptors (Cope et al, 2006; Denti et al, 2006; Peth et al, 2007; Schmidt et al, 2009; Enchev et al, 2012; Pierce et al, 2013; Zemla et al, 2013; Wu et al, 2013, reviewed in Wei et al, 2008). Deregulation of the CRL-CSN pathway causes misregulation of numerous important cellular targets and has been implicated in the development of some cancers (reviewed in Gummlich et al, 2013).