RAP-2 and CNH-MAP4 Kinase MIG-15 confer resistance in bystander epithelium to cell- fate transformation by excess Ras or Notch activity

• 成果类型: Article
• 署名作者: Fakieh, Razan A.; Reiner, David J.
• 署名单位: Texas A&M University System; Imam Abdulrahman Bin Faisal University; Texas A&M University System; Texas A&M University College Station; Texas A&M Health Science Center
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11300
• DOI: 10.1073/pnas.24143211211
• 发表日期: 2025-01-07
• 关键词: mediated down-regulation; vulval induction; putative effector; pattern-formation; lin-12/notch; activation; signal; inhibition; pathways; switch

摘要

Induction of cell fates by growth factors impacts many facets of developmental biology and disease. LIN-3/EGF induces the equipotent vulval precursor cells (VPCs) in Caenorhabditis elegans to assume the 3 & ring;-3 & ring;-2 & ring;-1 & ring;-2 & ring;-3 & ring; pattern of cell fates. 1 & ring; and 2 & ring; cells become specialized epithelia and undergo stereotyped series of cell divisions to form the vulva. Conversely, 3 & ring; cells are relatively quiescent and nonspecialized; they divide once and fuse with the surrounding epithelium. 3 & ring; cells have thus been characterized as passive, uninduced, or ground state. Based on our previous studies, we hypothesized that a 3 & ring;-promoting program would confer resistance to cell fate-transformation by inappropriately activated 1 & ring; and 2 & ring; fate-promoting LET-60/Ras and LIN-12/Notch, respectively. Deficient MIG-15/CNH-MAP4 Kinase meets the expectations of genetic interactions for a 3 & ring;-promoting protein. Moreover, endogenous MIG-15 is required for expression of a fluorescent biomarker of 3 & ring; cell fate, is expressed in VPCs, and functions cell autonomously in VPCs. The Ras family small GTPase RAP-2, orthologs of which activate orthologs of MIG-15 in other systems, emulates these functions of MIG-15. However, gain of RAP-2 function has no effect on patterning, suggesting its activity is constitutive in VPCs. The 3 & ring; biomarker is expressed independently of the AC, raising questions about the cellular origin of 3 & ring;-promoting activity. Activated LET-60/Ras and LIN-12/Notch repress expression of the 3 & ring; biomarker, suggesting that the 3 & ring;-promoting program is both antagonized by as well as antagonizes 1 & ring;- and 2 & ring;- promoting programs. This study provides insight into developmental properties of cells historically considered to be nonresponding to growth factor signals.