Raf‐1 and B‐Raf proteins have similar regional distributions but differential subcellular localization in adult rat brain

Morice, C.; Nothias, Fatiha; König, Sandra; Vernier, Philippe; Baccarini, Manuela; Vincent, Jean‐Didier; Barnier, Jean Vianney

doi:10.1046/j.1460-9568.1999.00609.x

Cited by 54 publications

(50 citation statements)

References 59 publications

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“…Consistent with its mRNA and protein levels, the activity of Raf-1 in both PFC and hippocampus was weaker than that of B-Raf. Our protein expression studies are somewhat similar to those reported by Morice et al, 44 who found that immunolabeling of B-Raf (B98 kDa band) was higher in hippocampus than cortex. However, contrary to our results, they found similar levels of Raf-1 expression in both PFC and hippocampus.…”

Section: Discussionsupporting

confidence: 91%

“…33,43 Raf-1 gene expression has been detected in all cell lines and tissues examined, with highest levels in brain although mRNA signal for Raf-1 in the brain is much weaker than that of B-Raf. 33 More recently, Morice et al 44 have shown that at the cellular level, both Raf-1 and B-Raf immunostaining is mostly localized in neurons. They also found that both these proteins are localized not only within the same brain areas but also within the same cells in rat brain; however, the intensities of the immunostaining were different, depending upon the brain structure.…”

Section: Discussionmentioning

confidence: 99%

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ERK MAP kinase signaling in post-mortem brain of suicide subjects: differential regulation of upstream Raf kinases Raf-1 and B-Raf

Dwivedi

Rizavi

Conley³

et al. 2005

Mol Psychiatry

115

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The Raf kinases Raf-1 and B-Raf are upstream activators of the extracellular signal-regulated kinase (ERK)-signaling pathway and therefore participates in many physiological functions in brain, including neuronal survival and synaptic plasticity. Previously, we observed that activation of ERK-1/2, the downstream component of ERK signaling, is significantly reduced in post-mortem brain of suicide victims. The present study was undertaken to further examine whether suicide brain is also associated with abnormalities in upstream molecules in ERK signaling. The study was performed in prefrontal cortex (PFC) and hippocampus obtained from 28 suicide victims and 21 normal controls. mRNA levels of Raf-1, B-Raf, and cyclophilin were measured by quantitative RT-PCR. Protein levels of Raf-1 and B-Raf were determined by Western blot, whereas their catalytic activities were determined by immunoprecipitation and enzymatic assays. It was observed that the catalytic activity of B-Raf was significantly reduced in PFC and hippocampus of suicide subjects. This decrease was associated with a decrease in its protein, but not mRNA, level. On the other hand, catalytic activity, and mRNA and protein levels, of Raf-1 were not altered in post-mortem brain of suicide subjects. The observed changes were not related to confounding variables; however, Raf-1 showed a negative correlation with age. Also, the changes in B-Raf were present in all suicide subjects, irrespective of psychiatric diagnosis. Our results of selective reduction in catalytic activity and expression of B-Raf but not Raf-1 suggest that B-Raf may be playing an important role in altered ERK signaling in brain of suicide subjects, and thus in the pathophysiology of suicide.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

ERK MAP kinase signaling in post-mortem brain of suicide subjects: differential regulation of upstream Raf kinases Raf-1 and B-Raf

Dwivedi

Rizavi

Conley³

et al. 2005

Mol Psychiatry

115

View full text Add to dashboard Cite

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“…B-Raf expression shows the most diverse expression patterns of the Raf family members in the nervous system. It can be cellspecific within a neuronal tissue (Dugan et al 1999) and subcellular-specific within an individual cell (Derkinderen et al 1999;Morice et al 1999). In agreement with these reports, B-Raf displays a distinct cell-specific and subcellular expression pattern in the avian auditory epithelium.…”

Section: B-raf Is a Key Excitatory Link Between The Camp/ Pka And Erkmentioning

confidence: 65%

“…The structures appear to cluster around the borders of the hair cells. B-Raf is a cytoplasmic signaling protein and the expression of B-Raf can be restricted to distinct subcellular regions such as neuronal dendrites and cell bodies (Derkinderen et al 1999;Morice et al 1999). The punctate B-Raf structures may represent cytoplasmic B-Raf signaling complexes that clustered to discrete lumenal regions of supporting cells.…”

Section: B-raf Expression Is Localized To Supporting Cells In the Avimentioning

confidence: 99%

cAMP-induced Auditory Supporting Cell Proliferation is Mediated by ERK MAPK Signaling Pathway

Bell

Oberholtzer

2010

JARO

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Sensorineural hearing deficiencies result from the loss of auditory hair cells. This hearing loss is permanent in humans and mammals because hair cells are not spontaneously replaced. In other animals such as birds, this is not the case. Damage to the avian cochlea evokes proliferation of supporting cells and the generation of functionally competent replacement hair cells. Signal transduction pathways are clinically useful as potential therapeutic targets, so there is significant interest in identifying the key signal transduction pathways that regulate the formation of replacement hair cells. In a previous study from our lab, we showed that forskolin (FSK) treatment induces auditory supporting cell proliferation and formation of replacement hair cells in the absence of sound or aminoglycoside treatment. Here, we show that FSK-induced supporting cell proliferation is mediated by cell-specific accumulation of cyclic adenosine monophosphate (cAMP) in avian supporting cells and the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. By a combination of immunostaining and pharmacological analyses, we show that FSK treatment increases cAMP levels in avian auditory supporting cells and that several ERK MAP inhibitors effectively block FSK-induced supporting cell proliferation. Next, we demonstrate by Western blotting and immunostaining analyses the expression of several ERK MAPK signaling molecules in the avian auditory epithelium and the cell-specific expression of B-Raf in avian auditory supporting cells. Collectively, these data suggest that FSK-induced supporting cell proliferation in the avian auditory epithelium is mediated by increases of cAMP levels in supporting cells and the cell-specific expression of the ERK MAPK family member B-Raf in supporting cells.

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“…B-RAF KIN/KIN mice were created that express A-RAF under control of endogenous B-RAF promoter, and we expected that neurons would survive beyond the critical midgestation cell death phase. Because we had previously observed that B-RAF overexpression can mediate neurite outgrowth (47) and because B-RAF localizes to axons and dendrites in vivo (25), we wanted to study these aspects of B-RAF function in neuronal differentiation.…”

mentioning

confidence: 99%

Cortical Migration Defects in Mice Expressing A-RAF from the B-RAF Locus

Camarero

Tyrsin

Xiang

et al. 2006

Molecular and Cellular Biology

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We have previously shown that mice lacking the protein kinase B-RAF have defects in both neural and endothelial cell lineages and die around embryonic day 12 (E12). To delineate the function of B-RAF in the brain, B-RAF KIN/KIN mice lacking B-RAF and expressing A-RAF under the control of the B-RAF locus were created. B-RAF KIN/KIN embryos displayed no vascular defects, no endothelial and neuronal apoptosis, or gross developmental abnormalities, and a significant proportion of these animals survived for up to 8 weeks. Cell proliferation in the neocortex was reduced from E14.5 onwards. Newborn cortical neurons were impaired in their migration toward the cortical plate, causing a depletion of Brn-2-expressing pyramidal neurons in layers II, III, and V of the postnatal cortex. Our data reveal that B-RAF is an important mediator of neuronal survival, migration, and dendrite formation and that A-RAF cannot fully compensate for these functions.The founding member of the RAF family of protein serine/ threonine kinases was discovered as the oncogene of mouse sarcoma virus 3611 (35). In vertebrate species, three RAF genes (A-RAF, B-RAF, and C-RAF) have been identified (5,14). B-RAF-deficient mice die between embryonic day 11.5 (E11.5) and E12.5 due to vascular hemorrhaging caused by increased apoptosis of endothelial cells (50). These animals also suffer from neuronal cell death (46) and a range of other defects that arise as a consequence of a significant disruption to ERK activation in these cells (48). Our earlier work further established that B-RAF is the major MEK activator in vivo and that C-RAF is required for normal B-RAF function (48). Targeted disruption of A-RAF or C-RAF genes demonstrated that their functions are not fully redundant with B-RAF, since null mutations for each gene resulted in distinct phenotypes (18,24,30,(48)(49)(50).Knock-in experiments support an important role of C-RAF in apoptosis suppression (6,18,53). The presence of multiple interaction partners of RAF that have been implicated in the control of apoptosis (36) and genetic experiments (18,24,48) raise the possibility that modulation of C-RAF kinase activity in survival depends on interaction with a different set of proteins, including Bcl-2 and Bag1 (11,12,43,44). A-RAF, the least well-characterized member of the family, appears to have the lowest specific activity for MEK (32, 51), although it clearly functions as a transforming gene and activates the mitogenic cascade when overexpressed in an activated form (17, 41). Moreover, like B-and C-RAF, A-RAF activation is coupled to stimulation of growth factor receptors such as nerve growth factor and epidermal growth factor receptors and expression of activated variants of all three isozymes causes differentiation and neurite formation in PC12 pheochromocytoma cells (47).Before determination of differentiated cell lineages in midgestation, C-RAF alone can fully compensate B-RAF function and vice versa (18,24,49,50). Double knockout experiments demonstrate that A-RAF alone cannot compensate B-...

show abstract

Raf‐1 and B‐Raf proteins have similar regional distributions but differential subcellular localization in adult rat brain

Cited by 54 publications

References 59 publications

ERK MAP kinase signaling in post-mortem brain of suicide subjects: differential regulation of upstream Raf kinases Raf-1 and B-Raf

ERK MAP kinase signaling in post-mortem brain of suicide subjects: differential regulation of upstream Raf kinases Raf-1 and B-Raf

cAMP-induced Auditory Supporting Cell Proliferation is Mediated by ERK MAPK Signaling Pathway

Cortical Migration Defects in Mice Expressing A-RAF from the B-RAF Locus

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