Related Experiment Video

Updated: Aug 5, 2025

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
11:32

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter

Published on: March 27, 2020

7.0K

NEK1-Mediated Phosphorylation of YAP1 Is Key to Prostate Cancer Progression

Ishita Ghosh1, Md Imtiaz Khalil1, Rusella Mirza2

  • 1Department of Biochemistry and Molecular Biology, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA.

Biomedicines
|March 29, 2023
PubMed

Insights

Understanding how prostate cancer cells become androgen-independent is key. A novel Hippo pathway axis (AR>TLK1B>NEK1>pYAP1-Y407) drives this progression, offering new therapeutic targets for metastatic castration-resistant prostate cancer (mCRPC).

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Signaling

Background:

  • Metastatic castration-resistant prostate cancer (mCRPC) progression involves androgen-dependent prostate cancer (PCa) cells developing independence and altering their gene expression.
  • Understanding the molecular mechanisms driving this transition is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To identify and characterize a novel signaling axis in the Hippo pathway involved in PCa adaptation to androgen deprivation and progression to CRPC.
  • To investigate the role of the TLK1B>NEK1>pYAP1-Y407 cascade in mediating transcriptional reprogramming and driving androgen-independent growth and epithelial-mesenchymal transition (EMT).

Main Methods:

  • Investigated a novel kinase cascade: androgen receptor (AR) signaling, TLK1B, NEK1, and YAP1 phosphorylation at Y407.
  • Utilized cell culture models (Hek293, LNCaP) with YAP1 mutants and overexpression, and NEK1 haploinsufficient TRAMP mice.
  • Employed immunohistochemistry on prostate cancer biopsies and tested a pharmacological inhibitor (J54) targeting the TLK1>NEK1>YAP1 nexus.

Main Results:

  • The AR->TLK1B>NEK1>pYAP1-Y407 axis promotes CRPC adaptation. YAP1-Y407 phosphorylation increases with androgen deprivation or DNA damage, mediated by NEK1.
  • YAP1-Y407F mutant expression reduces TEAD- and p73-regulated genes, conferring sensitivity to DNA damage. NEK1 haploinsufficiency in mice prevents carcinoma progression.
  • YAP1 overexpression transforms LNCaP cells to androgen-independent growth with mesenchymal morphology. Elevated pYAP1-Y407 nuclear signal correlates with high Gleason score (GS) in biopsies.
  • The inhibitor J54 suppresses androgen-independent growth and EMT progression by targeting the TLK1>NEK1>YAP1 nexus.

Conclusions:

  • The novel Hippo pathway axis, particularly the NEK1-mediated phosphorylation of YAP1 at Y407, is a critical driver of prostate cancer progression to castration resistance.
  • Targeting this axis, for example with J54, represents a promising therapeutic strategy to inhibit mCRPC growth and EMT.
Keywords:
AREMTNEK1TLKYAP1prostate cancer

More Related Videos

Combined Use of Tail Vein Metastasis Assays and Real-Time In Vivo Imaging to Quantify Breast Cancer Metastatic Colonization and Burden in the Lungs10:32

Combined Use of Tail Vein Metastasis Assays and Real-Time In Vivo Imaging to Quantify Breast Cancer Metastatic Colonization and Burden in the Lungs

Published on: December 19, 2019

11.0K
All-optical Mechanobiology Interrogation of Yes-associated Protein in Human Cancer and Normal Cells using a Multi-functional System09:55

All-optical Mechanobiology Interrogation of Yes-associated Protein in Human Cancer and Normal Cells using a Multi-functional System

Published on: December 20, 2021

3.0K

Related Concept Videos

mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.8K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.6K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.3K
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
5.7K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.8K
The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
6.3K