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The Ras Gene02:38

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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.
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Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
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Phosphorylation01:02

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The addition or removal of phosphate groups from proteins is the most common chemical modification that regulates cellular processes. These modifications can affect the structure, activity, stability, and localization of proteins within cells as well as their interactions with other proteins.
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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...
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Rab10 Phosphorylation Detection by LRRK2 Activity Using SDS-PAGE with a Phosphate-binding Tag
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Phosphorylation Protects Oncogenic RAS from LZTR1-Mediated Degradation.

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Researchers discovered a new way cancer cells control RAS protein stability, finding that blood cancers are particularly vulnerable to targeting this mechanism for therapy.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Oncogenic KRAS and NRAS mutations are prevalent in hematologic malignancies, yet their signaling pathways remain less understood compared to carcinomas.
  • Identifying regulators of RAS activity is crucial for uncovering novel biology and therapeutic vulnerabilities in these cancers.

Purpose of the Study:

  • To identify novel regulators of RAS activity in multiple myeloma using a multi-omics screening approach.
  • To investigate the mechanisms governing RAS protein stability and explore potential therapeutic strategies targeting these pathways in hematologic cancers.

Main Methods:

  • Multi-omics screening in multiple myeloma models.
  • Analysis of RAS protein dephosphorylation and degradation pathways.
  • Investigation of the role of PP1C, LZTR1, PAK1, and PAK2 in RAS regulation.
  • Comparison of RAS protein stability in hematologic versus carcinoma cells.

Main Results:

  • PP1C dephosphorylates RAS at T148, enabling LZTR1-mediated proteasomal degradation.
  • LZTR1 is ineffective against KRAS A146 gain-of-function mutations common in hematologic cancers.
  • KRAS protein exhibits four-fold lower stability in hematologic cells compared to carcinoma cells.
  • PAK1 and PAK2 phosphorylate T148, shielding RAS from LZTR1 degradation; targeting PAK1/2 enhances RAS-directed therapy.

Conclusions:

  • A novel regulatory circuit controlling RAS stability, preferentially active in blood cancers, has been identified.
  • This circuit involves PP1C, LZTR1, PAK1, and PAK2, offering potential therapeutic vulnerabilities.
  • Targeting RAS protein stability mechanisms presents a unique therapeutic opportunity for hematologic malignancies.