C-Fos Posttranslational Modifications

Phosphorylation

c-Fos serine/threonine (ser/thr) phosphorylation has been extensively studied in the past two decades (Herdegen and Leah, 1998; Jacobs et al., 1999) linking this phenomenon to protein stability (Gius et al., 1990; Tsurumi et al., 1995), signal transduction (Stork, 2002; Tanos et al., 2005) and transactivation capacity (Allegretto et al., 1990; Abate et al., 1993). From Portal et al 2006 PMID 17160021 for the references

tyrosine 10 and tyrosine 30

From Portal et al 2006 PMID 17160021

Fetal bovin serum causes rapid dephosphorylation of phospho-tyrosine c-Fos (this is the opposite of activation-induced ser/thr phosphorylation)

Effect

phosphotyrosine keeps c-Fos in the soluble fraction; dephosphorylation causes c-Fos to associate with endoplasmic reticulum (important for c-Fos-dependent activation of phospholipid synthesis)

Regulation

phosphorylation is increased with phenylarsine oxide (PAO), an inhibitor of tyr phosphatases

Sumoylation

The SUMO pathway resembles that of ubiquitin (24, 27, 36). It utilizes a single heterodimeric E1 SUMO-activating enzyme, Sae1/Sae2, and one E2 SUMO-conjugating enzyme, Ubc9. Although SUMO E1 and E2 are usually sufficient for sumoylation of substrates in vitro, a third component, E3, is also likely to be used in vivo for substrate selection and to ensure the specificity of reaction.

lysine 265

From Bossis et al 2005 PMID 16055710

Site

Conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3.

"We noted that c-Fos contains a psi-KXE (where psi is a large hydrophobic residue, K the conjugated lysine, E glutamic acid, and X any amino acid) consensus motif (45) for conjugation by SUMO, a peptidic posttranslational modifier structurally related to ubiquitin and conjugated on acceptor lysines.

Effect

Decreases transcriptional activity of c-Fos/c-Jun dimers. "The lower activity of sumoylated c-Fos is not due to inhibition of protein entry into the nucleus, accelerated turnover, and intrinsic inability to dimerize or to bind to DNA. Instead, cell fractionation experiments suggest that decreased transcriptional activity of sumoylated c-Fos is associated with specific intranuclear distribution.

Regulation

Inhibited by phosphorylation (by an unknown kinase) at threonine 232

Erk1/2 and Rsk1/2 kinases in this process. The use of kinase inhibitors revealed no role for the Erk1/2 and Rsk1/2 kinases, or the phosphatidyl- inositol 3-kinase/Akt, Jnk, and P38/SAPK pathways in the reduction of c-Fos sumoylation.

Myristylation

Oncogenic FBR v-Fos is myristylated, but c-Fos is not.

From Jotte and Holt 1996 PMID 8896601

"FBR v-fos is expressed as a 75-kD nuclear protein that differs from c-Fos by deletion and replacement of both NH2- and COOH-terminal regions with retroviral gag and mouse fox sequences, respectively....FBR v-los (Jotte et al., 1994). The altered transcrip- tional properties of FBR v-fos are dependent upon its myristylated NH2-terminal glycine."