fig1

Figure 1. TLK1’s role in mediating mCRPC progression and therapy resistance. (A) androgen deprivation therapy (ADT) blocks androgen receptor (AR) nuclear localization resulting in FKBP5 downregulation, which in turn, leads to AKT activation due to reduced dephosphorylation activity of PHLPP. AKT activation leads to mTORC1 activation, which activates 4EBP1 and releases eIF4E. Excess eIF4E initiates the translation of TLK1B. (B) TLK1/1B activates NEK1 by T141 phosphorylation, which in turn, activates ATR>Chk1>DNA damage response (DDR) signaling cascade. Activation of DDR promotes DNA repair inflicted by DNA damaging therapeutic agents. (C) TLK1>NEK1 axis is involved in VDAC1 S193 phosphorylation which maintains mitochondrial membrane integrity and suppresses intrinsic apoptotic signaling. (D) TLK1>NEK1 signaling phosphorylates YAP on Y407 and T493 residues and promotes the stabilization of YAP by binding to TEAD or other transcription factors (TF), leading to nuclear relocalization escaping proteasomal degradation. YAP stabilization and accumulation lead to CRPC progression and drug resistance. (E) TLK1 directly phosphorylates AKTIP on T22 and S237 residues, which stimulates AKT phosphorylation and activation, resulting in pro-survival and pro-migratory signaling. (F) TLK1 directly interacts and phosphorylates MK5, which increases its catalytic activity towards HSP27 (an MK5 substrate) and leads to increased migration and invasion, hence, metastasis of PCa cells.