Fam65b Is a New Transcriptional Target of FOXO1 That Regulates RhoA Signaling for T Lymphocyte Migration

Rougerie, Pablo; Largeteau, Quitterie; Megrelis, Laura; Carrette, Florent; Lejeune, Thomas; Toffali, Lara; Rossi, Barbara; Zeghouf, Mahel; Cherfils, Jacqueline; Constantin, Gabriela; Laudanna, Carlo; Bismuth, Georges; Mangeney, Marianne; Delon, Jérôme

doi:10.4049/jimmunol.1201174

Cited by 37 publications

(55 citation statements)

References 33 publications

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“…1B). Recently, Rougerie et al have shown that FAM65B directly binds to and inhibits RHOA (Rougerie et al, 2013). We confirmed that FAM65B was a potent inhibitor of RHOA, because FAM65B overexpression reduced the amount of active RHOA detected by the RBD pulldown assay (supplementary material Fig.…”

Section: Resultssupporting

confidence: 69%

“…It directly binds to RHOA and blocks the loading of GTP to RHOA. It was also shown that it has a role in chemokine-stimulated migration and adhesion of Jurkat cells (Rougerie et al, 2013). In this study, we confirm FAM65B as being a RHOA inhibitor.…”

Section: Introductionsupporting

confidence: 72%

“…It belongs to the FAM65 family of proteins, which is also includes FAM65A and FAM65C. Recently, FAM65B has been shown to be a RHOA inhibitor (Rougerie et al, 2013). It directly binds to RHOA and blocks the loading of GTP to RHOA.…”

Section: Introductionmentioning

confidence: 99%

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Front Signal-Dependent Accumulation of RHOA Inhibitor FAM65B at Leading Edges Polarizes Neutrophils

Gao

Tang

et al. 2015

Journal of Cell Science

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A hallmark of neutrophil polarization is the back localization of active RHOA and phosphorylated myosin light chain (pMLC, also known as MYL2). However, the mechanism for the polarization is not entirely clear. Here, we show that FAM65B, a newly identified RHOA inhibitor, is important for the polarization. When FAM65B is phosphorylated, it binds to 14-3-3 family proteins and becomes more stable. In neutrophils, chemoattractants stimulate FAM65B phosphorylation largely depending on the signals from the front of the cells that include those mediated by phospholipase Cb (PLCb) and phosphoinositide 3-kinase c (PI3Kc), leading to FAM65B accumulation at the leading edge. Concordantly, FAM65B deficiency in neutrophils resulted in an increase in RHOA activity and localization of pMLC to the front of cells, as well as defects in chemotaxis directionality and adhesion to endothelial cells under flow. These data together elucidate a mechanism for RHOA and pMLC polarization in stimulated neutrophils through direct inhibition of RHOA by FAM65B at the leading edge.

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Section: Resultssupporting

confidence: 69%

Section: Introductionsupporting

confidence: 72%

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Front Signal-Dependent Accumulation of RHOA Inhibitor FAM65B at Leading Edges Polarizes Neutrophils

Gao

Tang

et al. 2015

Journal of Cell Science

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“…Yeast two-hybrid experiments suggested that FAM65B interacts with NCAM (MIM116930), a membrane-bound glycoprotein that plays a role in cell-cell and cell-matrix adhesion, which is consistent with a role of FAM65B in myoblast fusion (19). In T lymphocytes, FAM65B down-regulates adhesion, polarization, and migration (21). This effect appears to be mediated by inhibition of RHOA (MIM165390), a protein that regulates remodeling of the actin cytoskeleton during cell morphogenesis and hence influences motility.…”

Section: Fam65b Is Present In Apical Plasma Membrane Of Mammalian Hairmentioning

confidence: 54%

FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing

Diaz‐Horta

Subasioglu-Uzak

Grati³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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In a large consanguineous Turkish kindred with recessive nonsyndromic, prelingual, profound hearing loss, we identified in the gene FAM65B (MIM611410) a splice site mutation (c.102-1G>A) that perfectly cosegregates with the phenotype in the family. The mutation leads to exon skipping and deletion of 52-amino acid residues of a PX membrane localization domain. FAM65B is known to be involved in myotube formation and in regulation of cell adhesion, polarization, and migration. We show that wild-type Fam65b is expressed during embryonic and postnatal development stages in murine cochlea, and that the protein localizes to the plasma membranes of the stereocilia of inner and outer hair cells of the inner ear. The wild-type protein targets the plasma membrane, whereas the mutant protein accumulates in cytoplasmic inclusion bodies and does not reach the membrane. In zebrafish, knockdown of fam65b leads to significant reduction of numbers of saccular hair cells and neuromasts and to hearing loss. We conclude that FAM65B is a plasma membrane-associated protein of hair cell stereocilia that is essential for hearing.deafness | whole-exome sequencing | congenital | Mendelian disorder | sensorineural H earing loss is the most common sensory problem, affecting approximately 1 in 500 newborns. Most cases are the consequence of mutations in single genes with specific functions in the inner ear (1) (http://hereditaryhearingloss.org). Hearing depends on the ability of the inner ear to convert acoustic waves into electrical signals. This process originates in the stereocilia, actin-rich structures that project from the apical pole of cochlear hair cells and are interconnected in the shape of a staircase to form the hair bundle. Most of the ∼50 hair-bundle proteins identified so far are the products of genes that when mutated lead to hearing loss (2). Thus, the genetic approach has played a major role in elucidating the molecular components of normal hearing.Here we present Family With Sequence Similarity 65, Member B (FAM65B, MIM611410) as a previously unrecognized, plasma membrane-associated protein of hair cell stereocilia. The critical role of FAM65B in human hearing was revealed by genetic analysis of a large family with hereditary deafness. In the zebrafish, knocking down the ortholog of FAM65B led to sensorineural hearing loss. Results A Splice Site Mutation in FAM65B Causes Profound SensorineuralHearing Loss in a Turkish Family. In a large consanguineous kindred of Turkish origin (Fig. 1A), six affected individuals had symmetric profound sensorineural hearing loss (Fig. 1B). Anamnestic evaluation and audiograms indicated congenital/prelingual onset hearing loss in all affected individuals. Available audiograms do not suggest progression of hearing loss. Transient evoked otoacoustic emissions and acoustic reflexes were negative in all affected members of the family. Auditory brainstem responses were absent as well. Affected individuals had neither delay in gross motor development nor balance problems, vertigo, dizziness, or n...

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“…Notably, most of the studies describe proadhesive signaling events, even when antiadhesive signals likely have an equally relevant role in leukocyte recruitment, for example, during the on-off turnover of integrin activation necessary for cell motility and transmigration. To date, few signaling molecules have been shown to negatively regulate leukocyte integrin activation; these include PKA (34), RHOH (35), CDC42 (10,36), SRC (37-39), H-RAS (40), ILK (41), FAM65B (42), and CAPN2 (43), with only CDC42 investigated according to the previously formalized four criteria (2). In the present study, fully compliant with these criteria, we show that PTPRG is a novel negative regulator of LFA-1 high-affinity-state triggering and mediated arrest by chemoattractants in human primary monocytes.…”

Section: Discussionmentioning

confidence: 99%

Protein Tyrosine Phosphatase Receptor Type γ Is a JAK Phosphatase and Negatively Regulates Leukocyte Integrin Activation

Mirenda

Toffali

Montresor

et al. 2015

The Journal of Immunology

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Regulation of signal transduction networks depends on protein kinase and phosphatase activities. Protein tyrosine kinases of the JAK family have been shown to regulate integrin affinity modulation by chemokines and mediated homing to secondary lymphoid organs of human T lymphocytes. However, the role of protein tyrosine phosphatases in leukocyte recruitment is still elusive. In this study, we address this issue by focusing on protein tyrosine phosphatase receptor type γ (PTPRG), a tyrosine phosphatase highly expressed in human primary monocytes. We developed a novel methodology to study the signaling role of receptor type tyrosine phosphatases and found that activated PTPRG blocks chemoattractant-induced β2 integrin activation. Specifically, triggering of LFA-1 to high-affinity state is prevented by PTPRG activation. High-throughput phosphoproteomics and computational analyses show that PTPRG activation affects the phosphorylation state of at least 31 signaling proteins. Deeper examination shows that JAKs are critically involved in integrin-mediated monocyte adhesion and that PTPRG activation leads to JAK2 dephosphorylation on the critical 1007–1008 phosphotyrosine residues, implying JAK2 inhibition and thus explaining the antiadhesive role of PTPRG. Overall, the data validate a new approach to study receptor tyrosine phosphatases and show that, by targeting JAKs, PTPRG downmodulates the rapid activation of integrin affinity in human monocytes, thus emerging as a potential novel critical regulator of leukocyte trafficking.

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Fam65b Is a New Transcriptional Target of FOXO1 That Regulates RhoA Signaling for T Lymphocyte Migration

Cited by 37 publications

References 33 publications

Front Signal-Dependent Accumulation of RHOA Inhibitor FAM65B at Leading Edges Polarizes Neutrophils

Front Signal-Dependent Accumulation of RHOA Inhibitor FAM65B at Leading Edges Polarizes Neutrophils

FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing

Protein Tyrosine Phosphatase Receptor Type γ Is a JAK Phosphatase and Negatively Regulates Leukocyte Integrin Activation

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