Biomedical subjects

Claudia Figueroa

Publications and source records attributed to Claudia Figueroa.

4 recordsLinked to original sources

PubMed2006

UNC-51-like kinase regulation of fibroblast growth factor receptor substrate 2/3.

UNC-51-like kinases (ULK) are members of an evolutionarily conserved sub-family of ubiquitously expressed serine/threonine-specific protein kinases. Here we report that fibroblast growth factor receptor substrate (FRS) 2/3 are novel ULK2 carboxy-terminal domain interacting proteins. FRS2/3 are homologs that function as adaptor proteins to mediate signaling of multiple receptor tyrosine kinases. ULK2 interacts with the phospho-tyrosine binding (PTB) domain of FRS2/3. We demonstrate that siRNA targeting ULK2 in mouse P19 cells results in elevated FGFR1 mediated FRS3 and SHP2 tyrosyl phosphorylation. In addition, RNAi-mediated decrease in ULK2 causes increased interaction between FGFR1 and FRS3. ULK2 phosphorylates FRS2/3 in vitro, suggesting that ULK2 mediated phosphorylation may be a mechanism of FRS2/3 regulation. The data presented support a model in which ULK2, by interaction with FRS2/3 and inhibition of SynGAP, functions to negatively regulate tyrosyl phosphorylation of signaling proteins downstream of FGFR1.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Akt2 negatively regulates assembly of the POSH-MLK-JNK signaling complex.

We demonstrate that POSH, a scaffold for the JNK signaling pathway, binds to Akt2. A POSH mutant that is unable to bind Akt2 (POSH W489A) exhibits enhanced-binding to MLK3, and this increase in binding is accompanied by increased activation of the JNK signaling pathway. In addition, we show that the association of MLK3 with POSH is increased upon inhibition of the endogenous phosphatidylinositol 3-kinase/Akt signaling pathway. Thus, the assembly of an active JNK signaling complex by POSH is negatively regulated by Akt2. Further, the level of Akt-phosphorylated MLK3 is reduced in cells expressing the Akt2 binding domain of POSH, which acts as a dominant interfering protein. Taken together, our results support a model in which Akt2 binds to a POSH-MLK-MKK-JNK complex and phosphorylates MLK3; phosphorylation of MLK3 by Akt2 results in the disassembly of the JNK complex bound to POSH and down-regulation of the JNK signaling pathway.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Akt negatively regulates translation of the ternary complex factor Elk-1.

Cross-talk between signaling pathways plays an important role in regulation of cell growth, differentiation, survival, and death. Here, we show that Akt regulates the Elk-1 transcription factor, independent of its negative regulation of Raf kinases. Using a constitutively active Mek1 to bypass the regulation of Raf by Akt, we find that the Elk-1 and Sap1a proteins are dramatically decreased in the presence of activated Akt. Akt catalytic activity is required. Also, Mek-dependent activation of a TCF (Elk-1/Sap-1a)-dependent c-fos reporter is decreased by activated Akt. Neither the level of Elk-1 mRNA nor the stability of the Elk-1 protein is altered by activated Akt. Instead, the rate of incorporation of labeled methionine into Elk-1 protein is decreased in the presence of Akt. In addition, the level of the Elk-1 protein but not GFP is significantly decreased in the presence of activated Akt, when GFP is expressed from an IRES element in a bicistronic message with Elk-1. We conclude that Akt negatively regulates translation of the Elk-1 mRNA. A coding region determinant that maps within the first 279 nts of the Elk-1 message is necessary and sufficient for Akt-mediated regulation of Elk-1.

Animals↗

PubMed2003

Akt regulates basic helix-loop-helix transcription factor-coactivator complex formation and activity during neuronal differentiation.

Neural basic helix-loop-helix (bHLH) transcription factors regulate neurogenesis in vertebrates. Signaling by peptide growth factors also plays critical roles in regulating neuronal differentiation and survival. Many peptide growth factors activate phosphatidylinositol 3-kinase (PI3K) and subsequently the Akt kinases, raising the possibility that Akt may impact bHLH protein function during neurogenesis. Here we demonstrate that reducing expression of endogenous Akt1 and Akt2 by RNA interference (RNAi) reduces neuron generation in P19 cells transfected with a neural bHLH expression vector. The reduction in neuron generation from decreased Akt expression is not solely due to decreased cell survival, since addition of the caspase inhibitor z-VAD-FMK rescues cell death associated with loss of Akt function but does not restore neuron formation. This result indicates that Akt1 and Akt2 have additional functions during neuronal differentiation that are separable from neuronal survival. We show that activated Akt1 enhances complex formation between bHLH proteins and the transcriptional coactivator p300. Activated Akt1 also significantly augments the transcriptional activity of the bHLH protein neurogenin 3 in complex with the coactivators p300 or CBP. In addition, inhibition of endogenous Akt activity by the PI3K/Akt inhibitor LY294002 abolishes transcriptional cooperativity between the bHLH proteins and p300. We propose that Akt regulates the assembly and activity of bHLH-coactivator complexes to promote neuronal differentiation.

Amino Acid Chloromethyl Ketones↗