Fig. 3

(A) CDK5 signaling in MTC. Upon Rb phosphorylation by CDK5, E2F is released and activates the transcription of target genes, including CDK2 and Cyclin A, that mediate cell proliferation. CDK2-Cyclin A further phosphorylates Rb in a positive feedback loop. HER2 signaling activates CDK5 by an unknown mechanism, which in turn phosphorylates STAT3 at S727, promoting cell proliferation and tumorigenesis through cFos-JunB signaling. GDNF activates RET signaling leading to ERK-EGR1 activation, which increases p35 transcription, increasing CDK5 activation. Active CDK5 phosphorylates STAT3 at S727, promoting tumorigenesis. Green circles show activating phosphorylation events. (B) CDK5-mediated signaling pathways in gastric and colorectal cancer. In gastric cancer, nuclear CDK5 overexpression inhibits the proliferation and metastasis of gastric cancer cells. Nuclear CDK5 upregulates the CDK inhibitor p16INK4a, which inhibits the S-G2 phase transition, leading to cell cycle arrest. CDK5 binds with p27, which results in its nuclear translocation. CDK5 also binds PP2A, which inhibits metastasis; however, it is unknown whether this event occurs in the cytoplasm and/or nucleus. (C) CDK5 modulates the ERK5–AP-1 axis to regulate the oncogenic pathway in colorectal cancer. CDK5 directly interacts with ERK5 and phosphorylates it at T732, thus upregulating the expression of AP-1 and some of its target genes (VEGFA, MMP1 and c-myc). This event results in the malignant development of human CRC both in vitro and in vivo