Mixed-lineage kinase 3 regulates B-Raf through maintenance of the B-Raf/Raf-1 complex and inhibition by the NF2 tumor suppressor protein

Proceedings of the National Academy of Sciences of the United States of America
Deborah N ChadeeJ M Kyriakis

Abstract

The Ras --> Raf --> MEK1/2 --> extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway couples mitogenic signals to cell proliferation. B-Raf and Raf-1 function within an oligomer wherein they are regulated in part by mutual transactivation. The MAPK kinase kinase (MAP3K) mixed-lineage kinase 3 (MLK3) is required for mitogen activation of B-Raf and cell proliferation. Here we show that the kinase activity of MLK3 is not required for support of B-Raf activation. Instead, MLK3 is a component of the B-Raf/Raf-1 complex and is required for maintenance of the integrity of this complex. We show that the activation of ERK and the proliferation of human schwannoma cells bearing a loss-of-function mutation in the neurofibromatosis 2 (NF2) gene require MLK3. We find that merlin, the product of NF2, blunts the activation of both ERK and c-Jun N-terminal kinase (JNK). Finally, we demonstrate that merlin and MLK3 can interact in situ and that merlin can disrupt the interactions between B-Raf and Raf-1 or those between MLK3 and either B-Raf or Raf-1. Thus, MLK3 is part of a multiprotein complex and is required for ERK activation. The levels of this complex may be negatively regulated by merlin.

References

Jul 1, 1997·Nature Genetics·L WojnowskiA Zimmer
Apr 11, 2001·The EMBO Journal·M HüserC Pritchard
Apr 28, 2001·The Journal of Biological Chemistry·A C MaroneyJ L Vaught
Nov 13, 2001·Developmental Cell·R J ShawA I McClatchey
Sep 5, 2002·Nature Reviews. Molecular Cell Biology·Kathleen A Gallo, Gary L Johnson
Jan 25, 2003·Current Opinion in Neurology·Michael E BaserDavid H Gutmann
Jun 5, 2003·Biochimica Et Biophysica Acta·Kathryn E Mercer, Catrin A Pritchard
Dec 12, 2003·Nature Reviews. Cancer·Andrea I McClatchey
Mar 24, 2004·Cell·Paul T C WanUNKNOWN Cancer Genome Project
Jul 20, 2004·Nature Cell Biology·Deborah N Chadee, John M Kyriakis
Apr 16, 2005·Molecular and Cellular Biology·Deborah BranchoRoger J Davis
Apr 27, 2012·Physiological Reviews·John M Kyriakis, Joseph Avruch

❮ Previous
Next ❯

Citations

Aug 8, 1984·Biochimica Et Biophysica Acta·M A MarkwellL Svennerholm
Jul 31, 2012·Nature Genetics·Michael KrauthammerRuth Halaban
May 15, 2007·Oncogene·A Clapéron, M Therrien
Dec 4, 2009·Human Molecular Genetics·Sérgia VelhoRaquel Seruca
Jul 19, 2008·Otology & Neurotology : Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology·J Jason ClarkMarlan R Hansen
Sep 8, 2007·Current Opinion in Otolaryngology & Head and Neck Surgery·D Bradley WellingLong-Sheng Chang
Dec 24, 2008·Molecular and Cellular Biology·S Sean HoushmandiDavid H Gutmann
Aug 25, 2012·American Journal of Physiology. Gastrointestinal and Liver Physiology·Pavlo L KovalenkoMarc D Basson
Jul 18, 2008·Cancer Research·Ying-Ka Ingar LauQin Yu
Jul 23, 2011·Genes & Cancer·David MatallanasWalter Kolch
Nov 1, 2011·Cell Communication and Signaling : CCS·Jens RauchWalter Kolch
May 4, 2010·Journal of Neurosurgery·Michael E SughrueMichael W McDermott
May 23, 2014·Nature Communications·Anna A MarusiakJohn Brognard
Oct 29, 2013·Experimental and Molecular Pathology·M A RahmanA K-Y Lam
Dec 12, 2012·Virchows Archiv : an International Journal of Pathology·Maurits de VriesPancras C W Hogendoorn
Sep 26, 2007·AJNR. American Journal of Neuroradiology·F J WippoldA Perry
May 1, 2013·Canadian Journal of Physiology and Pharmacology·Deborah N Chadee
Sep 8, 2010·Cellular and Molecular Life Sciences : CMLS·Christian M UdellMarc Therrien
Nov 6, 2007·Biochimica Et Biophysica Acta·Daniel R Scoles
Apr 20, 2007·Trends in Cell Biology·Tomoyo OkadaFilippo G Giancotti
Jan 9, 2007·Current Opinion in Genetics & Development·Nathalie Dhomen, Richard Marais
Apr 6, 2007·International Journal of Experimental Pathology·Matthew E HandleyDavid R Katz
Aug 9, 2006·International Journal of Cancer. Journal International Du Cancer·Ralf Schreck, Ulf R Rapp
Aug 14, 2012·The Laryngoscope·Brian A NeffHirohito Kita
Jul 22, 2014·Pigment Cell & Melanoma Research·Victoria J MarGrant A McArthur
Feb 18, 2010·The Biochemical Journal·Geou-Yarh LiouKathleen A Gallo
Aug 7, 2007·Molecular Cell·Anja Jaeschke, Roger J Davis
Oct 15, 2008·Molecular Cell·Katherine I Swenson-FieldsAnthony R Means
Sep 29, 2009·Biochimica Et Biophysica Acta·Eric T ColeDeborah N Chadee
May 24, 2016·Cancers·Chotirat Rattanasinchai, Kathleen A Gallo
Jul 20, 2016·ELife·Josipa RaguzManuela Baccarini
Feb 6, 2007·Biochimica Et Biophysica Acta·John M Kyriakis

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.