Related Experiment Video

Updated: May 8, 2026

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
06:09

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells

Published on: June 7, 2019

Somatic mutations in MAP3K5 attenuate its proapoptotic function in melanoma through increased binding to thioredoxin

Todd D Prickett1, Brad Zerlanko1, Jared J Gartner1

  • 1The Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

The Journal of Investigative Dermatology
|September 7, 2013
PubMed

Insights

Researchers discovered a new mutation in the MAP3K5 gene in melanoma patients. This mutation, R256C, may offer a new therapeutic target for advanced metastatic melanoma.

Area of Science:

  • Genomics
  • Oncology
  • Molecular Biology

Background:

  • Advanced metastatic melanoma has a poor prognosis.
  • The genetic underpinnings of melanoma pathogenesis are not fully understood.
  • High-throughput sequencing enables comprehensive somatic mutation discovery in cancer.

Purpose of the Study:

  • To identify recurrent somatic mutations in melanoma using whole-genome and whole-exome sequencing.
  • To investigate the functional impact of identified mutations.
  • To explore potential therapeutic targets for melanoma.

Main Methods:

  • Whole-genome and whole-exome sequencing of 29 melanoma samples.
  • Prevalence screening of MAP3K5 mutations in 288 melanoma samples.
  • Functional analysis of the MAP3K5 R256C mutation in melanoma cells.

Main Results:

  • Identified recurrent nonsynonymous mutations in several genes, including MAP3K5.
  • Found MAP3K5 R256C mutation in 5 out of 288 melanomas, exclusively in BRAF wild-type samples.
  • Demonstrated that MAP3K5 R256C mutation attenuates MKK4 activation via increased thioredoxin binding, promoting melanoma cell proliferation and growth.

Conclusions:

  • The MAP3K5 R256C mutation is a potential therapeutic target in melanoma.
  • MAP3K5 mutations may represent an alternative pathway to BRAF mutations in melanoma.
  • Understanding these genetic alterations can guide the development of novel melanoma treatments.

More Related Videos

The Three-Dimensional Human Skin Reconstruct Model: a Tool to Study Normal Skin and Melanoma Progression11:02

The Three-Dimensional Human Skin Reconstruct Model: a Tool to Study Normal Skin and Melanoma Progression

Published on: August 3, 2011

Screening for Melanoma Modifiers using a Zebrafish Autochthonous Tumor Model10:23

Screening for Melanoma Modifiers using a Zebrafish Autochthonous Tumor Model

Published on: November 13, 2012

Related Concept Videos

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 daughter...
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...
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
Microtubule Associated Proteins (MAPs)01:42

Microtubule Associated Proteins (MAPs)

Microtubule function and architecture are regulated by an array of specialized proteins called microtubule-associated proteins or MAPs. These proteins are widespread across different organisms and have conserved protein motifs, like the multi-TOG domain for tubulin binding found in the CLASP family of MAPs. Some MAPs are lineage-specific based on their conserved domains. Their functions depend upon the cytoskeletal architecture and cell type they are located within. In-plant cells, a specific...
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 rapamycin-insensitive companion...
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...