c-Fos Posttranslational Modifications

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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

Abate et al 1991 PMID 1766667 describes phosphorylation of c-Fos in vitro by PKA, PKC, and p34cdc2 (need to get the paper)

Abate et al 1993 PMID 8341696 describe regulation of c-fos phosphorylation by dimerization with c-Jun and binding to AP-1 oligo: phospho-c-Fos is not much regulated, although phospho- c-jun is altered by dimerization or DNA binding.

(need to put this in a nice table) kinase Fos fos/jun Fos/Jun/AP-1 cdc2 100 100 50 PKC 100 100 100 PKA 100 100 100 p44 mapk 100 100 100 DNA-PK 0 0 100

Ser374 and Ser362

From Pellegrino Stork 2006 PMID 17223854


In the C-terminus, can stabilize c-Fos by interfering with degradation, and act as 'priming' phosphorylations that help potentiate phosphorylation with the transactivation domain (Thr325, Thr331, and maybe Thr232)


Ser374 phosphorylated by ERKs in vitro and in vivo Chen 1996

Ser362 phosphorylated by ERK-dependent RSK, but NOT phosphorylated by ERK directly in vitro (Monje et al. 2003),.

Thr325 and Thr331

From Pellegrino Stork 2006 PMID 17223854


within the transactivation domain potentiate AP-1-dependent transcription (Monje et al. 2003)


phosphorylated by ERKs (although less sure about Thr331)

depends on the the binding of ERKs to an ERK targeting domain, also known as a DEF domain


From Pellegrino Stork 2006 PMID 17223854


enhances c-Fos transactivation


Thr232 is phosphorylated by unknown kinase (NOT ERK1/2)

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)


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)


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


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


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.


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.


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.




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."