Simultaneous hyperactivation of stress-activated protein kinase/c-Jun N-terminal protein kinase (SAPK/JNK) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling cascades has been reported in carcinogenesis. However, how they are integrated to promote oncogenesis remains unknown. By analyzing breast invasive carcinoma database (The Cancer Genome Altas), we found that the mRNA expression levels of both JNK1 and ERK2 are positively correlated with the mRNA level of EEA1, an endosome associated protein, indicating the potential JNK/ERK crosstalk at endosome. Unbiased screen of different endosome-associated Rab GTPases reveals that late endosome serves as a unique platform to integrate JNK/ERK signaling. Furthermore, we identify that BPGAP1 (a BCH domain-containing, Cdc42GAP-like Rho GTPase-activating protein) promotes MEK partner 1 (MP1)-induced ERK activation on late endosome through scaffolding MP1/MEK1 complex. This regulatory function requires phosphorylation of BPGAP1 by JNK at its C terminal tail (Ser424) to unlock its autoinhibitory conformation. Consequently, phosphorylated BPGAP1 facilitates endosomal ERK signaling transduction to the nucleus, driving cell proliferation and transformation via the ERK–Myc–CyclinA axis. BPGAP1 therefore provides a crucial spatiotemporal checkpoint where JNK and MP1/MEK1 work in concert to regulate endosomal and nuclear ERK signaling in cell proliferation control.
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This work was supported by an NUS Research Scholarship (to TJ), a Ministry of Education Tier 2 grant (R154-000-236-112 to BCL) and the Mechanobiology Institute of Singapore (to BCL), funded through the National Research Foundation and the Ministry of Education Singapore. This work was also supported by National Medical Research Council, CBRG New Investigator Grant (CBRG-NIG) (R-714-000-115-511 to CQP). We thank Proteins and Proteomics Center (National University of Singapore) for mass spectrometric analysis. We thank Nisha Mohd Rafiq (National University of Singapore) for the technical support. We also thank Professor Andrew Catling (LSU Health Sciences Center), Professor Kanga Sabapathy (National Cancer Center, Singapore), and Professor Yih-Cherng Liou (National University of Singapore) for providing MP1, phospho-JNK1, CyclinA and CyclinE antibodies, respectively.
TJ designed and performed the experiments. TJ and CQP analyzed the data. TJ and CQP wrote the paper. BCL designed experiments, analyzed data and wrote the paper.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Oncogene website
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ERK1/2 and JNK signaling synergistically modulate mitogenic effect of fibroblast growth factor 2 on liver cell
Cell Biology International (2018)