China
Africa
Explore chapters and articles related to this topic
Genetics and genomics of exposure to high altitude
Published in Andrew M. Luks, Philip N. Ainslie, Justin S. Lawley, Robert C. Roach, Tatum S. Simonson, Ward, Milledge and West's High Altitude Medicine and Physiology, 2021
Andrew M. Luks, Philip N. Ainslie, Justin S. Lawley, Robert C. Roach, Tatum S. Simonson
Putatively adaptive copies of the THRB gene region, as well as PPARA and EPAS1 identified in Tibetans (Simonson et al. 2010), show relationships with hemoglobin concentration in Amhara Ethiopians (Scheinfeldt et al. 2012). EDNRB (endothelial receptor B), previously reported as a top selection candidate in Andeans (Bigham et al. 2010), is also reported in Amhara Ethiopians, and knockdown of this gene increases hypoxia tolerance in mice (Udpa et al. 2014). The gene family member EDNRA is also a top candidate gene in Tibetans (Simonson et al. 2010). BHLHE41, although not associated with hemoglobin, is a key HIF pathway gene and top selection candidate in Amhara, Oromo, and Tigray Ethiopians (Huerta-Sánchez et al. 2013). In addition to these hypoxia-associated genes, three others (VAV3, which encodes vav guanine nucleotide exchange factor 3, and RORA that encodes the RAR-related orphan receptor A) are reported as top candidates in Amhara Ethiopians (Scheinfeldt et al. 2012). Whole-genome sequence analyses indicate three genes contained within the same region of chromosome 19 identified as adaptive targets in Oromo and Simen Ethiopians, CIC, LIPE, and PAFAH1B3 (that encode capicua transcriptional repressor, lipase E hormone-sensitive type, and platelet- activating factor acetylhydrolase 1b catalytic subunit 2, respectively) have orthologs in Drosophila that afford tolerance to hypoxia (Udpa et al. 2014).
The role of the prolactin receptor pathway in the pathogenesis of glioblastoma: what do we know so far?
Published in Expert Opinion on Therapeutic Targets, 2020
Antonela S Asad, Alejandro J Nicola Candia, Nazareno Gonzalez, Camila F Zuccato, Adriana Seilicovich, Marianela Candolfi
On the other hand, PRLR signaling also activates the Vav family of guanine nucleotide exchange factors [49]. Co-immunoprecipitation assays have demonstrated a PRL-dependent interaction of Nek3 with Vav1 and Vav2 [49]. Vav2 also contains two Src homology 3 and one Src homology 2 (SH3-SH2-SH3) domains, which are involved in the interaction between Vav2 and tyrosine-phosphorylated proteins [49]. The phosphorylation of Vav proteins by kinases such as Tec, Src family proteins, and JAK2 allows the activation of Rac1 and Rho proteins [49]. Moreover, Vav2 binds STAT5 and upregulates the activity of both Rac1 and STAT5 [49]. The Vav family has been proposed to be involved in the development of gliomas, since Vav3 was shown to mediate exchange for Rac1 in the promotion of glioma cell migration [51]. STAT5 can also be phosphorylated by Src proteins after PRLR activation [47]. It was shown that PRLR signaling allows the activation of ERK1/2 and PI3K by Src family members and hence the proliferation of breast cancer cells [52]. Similarly, PRL was found to activate Fyn, a member of the Src family kinases, in Nb2 cells [53]. In these cells, PRLR dimerization would be necessary for Fyn activation [53]. Fyn and Src have been proposed to be effectors of oncogenic EGFR signaling in GBM, enhancing invasion and tumor cell survival in vivo [54]. Insulin receptor substrate 1(IRS-1) would also associate to PRLR in a PRL-dependent manner, providing binding sites for SH2 domains of PI3K subunit p85, and activating PI3K via JAK2 kinase [48]. The overexpression of IRS1 was reported to decrease the sensitivity to the radiation in GBM cells [55].
Critical redundant functions of the adapters Grb2 and Gads in platelet (hem)ITAM signaling in mice
Published in Platelets, 2020
Timo Vögtle, Ayesha A. Baig, Julia Volz, Timothy B. Duchow, Irina Pleines, Sebastian Dütting, Lars Nitschke, Stephen P. Watson, Bernhard Nieswandt
Functional redundancies have been reported for other closely related proteins involved in the (hem)ITAM signaling complex. An absolute functional redundancy was observed in the case of Vav1 and Vav3 that, in addition to their function as guanine nucleotide exchange factors (GEFs), act as adapter proteins and play critical redundant roles in the activation of PLCγ2 downstream of GPVI [17]. In addition, we have previously shown that the Src-like adapter proteins SLAP and SLAP2 that negatively regulate (hem)ITAM signaling are functionally redundant [18]. Besides, there are also proteins within the (hem)ITAM signaling cascade that functionally compensate for each other in a way that one isoform plays a more important role than the other, as is the case for PLCγ isoforms, where PLCγ2 plays a predominant role in murine platelets [19]. Also, between the Tec kinases Btk and Tec, it is the former that plays a more prominent role in platelet activation through GPVI [20]. On the other hand, no functional homologs for Syk and Slp-76 are expressed in platelets [21].
The potential of AR-V7 as a therapeutic target
Published in Expert Opinion on Therapeutic Targets, 2018
Takuma Uo, Stephen R. Plymate, Cynthia C. Sprenger
The transcription factor FOXO1, a key downstream effector of PTEN, directly binds to the TAU-5 motif in AR, competes for binding of AR with coactivator SRC-1, and thereby inhibits NTD activity [57,58]. VAV3, a Rho GTPase guanine nucleotide exchange factor, acts as a coactivator of AR in CRPC through the interaction of its Dbl homology (DH) domain with the TAU-5 motif in AR [59]. The DH domain is a region on a protein that induces Rho family GTPases to displace GDP, thereby allowing GTP to bind [59]. Ectopic expression of VAV3 DH domain was able to disrupt the interaction between AR-V7 and its coactivator VAV2 that is paralogous to VAV3 [60]. Thus it is well rationalized to design peptidomimetics that compete with VAV proteins for binding to TAU5 in AR [60].