PTPH1 is a human protein-tyrosine phosphatase with homology to the band 4.1 superfamily of cytoskeletal-associated proteins.
PTPH1 was found to associate with 14-3-3β using a yeast two-hybrid screen, and its interaction could be reconstituted in vitro using recombinant proteins. Examination of the interaction between 14-3-3β and various deletion mutants of PTPH1 by two-hybrid
tests suggested that the integrity of the PTP is important for this binding. Although both PTPH1 and Raf-1 form complexes
with 14-3-3β, they appear to do so independently. Binding of 14-3-3β to PTPH1in vitro was abolished by pretreating PTPH1 with potato acid phosphatase and was greatly enhanced by pretreating with Cdc25C-associated
protein kinase. Thus the association between PTPH1 and 14-3-3β is phosphorylation-dependent. Two novel motifs RSLS359VE and RVDS853EP in PTPH1 were identified as major 14-3-3β-binding sites, both of which are distinct from the consensus binding motif RSXSXP recently found in Raf-1. Mutation of Ser359 and Ser853 to alanine significantly reduced the association between 14-3-3β and PTPH1. Furthermore, association of PTPH1 and 14-3-3β
was detected in several cell lines and was regulated in response to extracellular signals. These results raise the possibility
that 14-3-3β may function as an adaptor molecule in the regulation of PTPH1 and may provide a link between serine/threonine
and tyrosine phosphorylation-dependent signaling pathways.
"More than 200 binding proteins have been reported to interact with the 14-3-3 proteins. These include receptors (Furlanetto et al., 1997; Wakui et al., 1997), kinases (Bonnefoy-Berard et al., 1995; Freed et al., 1994; Reuther et al., 1994), phosphatases (Conklin et al., 1995; Zhang et al., 1997), docking molecules (Garcia-Guzman et al., 1999; Ogihara et al., 1997), cell death regulators (Vincenz & Dixit, 1996; Zha et al., 1996) and oncogene products (Pallas et al., 1994; Reuther et al., 1994). One of the most well-studied binding partners of 14-3-3 proteins is Raf-1 (Fantl et al., 1994; Freed et al., 1994; Fu et al., 1994; Irie et al., 1994; Li et al., 1995; McPherson et al., 1999), a shared effector of both Ras and Rap proteins. "
[Show abstract][Hide abstract] ABSTRACT: Ras and Rap proteins are closely related small guanosine triphosphatase (GTPases) that share similar effector-binding domains but operate in a very different signaling networks; Ras has a dominant role in cell proliferation, while Rap mediates cell adhesion. Ras and Rap proteins are regulated by several shared processes such as post-translational modification, phosphorylation, activation by guanine exchange factors and inhibition by GTPase-activating proteins. Sub-cellular localization and trafficking of these proteins to and from the plasma membrane are additional important regulatory features that impact small GTPases function. Despite its importance, the trafficking mechanisms of Ras and Rap proteins are not completely understood. Chaperone proteins play a critical role in trafficking of GTPases and will be the focus of the discussion in this work. We will review several aspects of chaperone biology focusing on specificity toward particular members of the small GTPase family. Understanding this specificity should provide key insights into drug development targeting individual small GTPases.
Critical Reviews in Biochemistry and Molecular Biology 12/2014; 50(3). DOI:10.3109/10409238.2014.989308 · 7.71 Impact Factor
"The MITF-S173A mutation did not affect interaction with C-TAK1 in coimmunoprecipitation experiments , and endogenous 14-3-3 was not observed (Figure 6A, lane 4). These results are consistent with C-TAK1 as a protein kinase that can phosphorylate MITF and enhance interactions with 14-3-3, as has been reported for several other C-TAK1 substrates (Zhang et al., 1997; Peng et al., 1998; Muller et al., 2001, 2003). A consensus sequence for recognition of substrates by C-TAK1 has been developed based on sequence alignment and mutagenesis studies (Supplemental Figure 4) (Muller et al., 2003). "
[Show abstract][Hide abstract] ABSTRACT: The microphthalmia-associated transcription factor (MITF) is required for terminal osteoclast differentiation and is a target for signaling pathways engaged by colony stimulating factor (CSF)-1 and receptor-activator of nuclear factor-kappaB ligand (RANKL). Work presented here demonstrates that MITF can shuttle from cytoplasm to nucleus dependent upon RANKL/CSF-1 action. 14-3-3 was identified as a binding partner of MITF in osteoclast precursors, and overexpression of 14-3-3 in a transgenic model resulted in increased cytosolic localization of MITF and decreased expression of MITF target genes. MITF/14-3-3 interaction was phosphorylation dependent, and Ser173 residue, within the minimal interaction region of amino acid residues 141-191, was required. The Cdc25C-associated kinase (C-TAK)1 interacted with an overlapping region of MITF. C-TAK1 increased MITF/14-3-3 complex formation and thus promoted cytoplasmic localization of MITF. C-TAK1 interaction was disrupted by RANKL/CSF-1 treatment. The results indicate that 14-3-3 regulates MITF activity by promoting the cytosolic localization of MITF in the absence of signals required for osteoclast differentiation. This work identifies a mechanism that regulates MITF activity in monocytic precursors that are capable of undergoing different terminal differentiation programs, and it provides a mechanism that allows committed precursors to rapidly respond to signals in the bone microenvironment to promote specifically osteoclast differentiation.
Molecular Biology of the Cell 10/2006; 17(9):3897-906. DOI:10.1091/mbc.E06-05-0470 · 4.47 Impact Factor
"In addition, the expression of several plant and mammalian isoforms is influenced by external stimuli like temperature, injury and different types of stress (Yaffe, 2002; Jarillo et al., 1994; de Vetten and Ferl, 1995; Chen et al., 1994; Kidou et al., 1993). Besides differences in expression patterns, there are several reports on isoform-specific interactions with 14-3-3 binding partners (Yaffe, 2002; Wakui et al., 1997; Craparo et al., 1997; Meller et al., 1996; Liu et al., 1997; Van Der Hoeven et al., 2000; Tang et al., 1998; Peng et al., 1997; Zhang et al., 1997; Kumagai et al., 1998; Kurz et al., 2000; Hashiguchi et al., 2000). However, many functions can be performed by all 14-3-3 isoforms. "
[Show abstract][Hide abstract] ABSTRACT: Nucleocytoplasmic transport of proteins plays an important role in the regulation of many cellular processes. Differences in nucleocytoplasmic shuttling can provide a basis for isoform-specific biological functions for members of multigene families, like the 14-3-3 protein family. Many organisms contain multiple 14-3-3 isoforms, which play a role in numerous processes, including signalling, cell cycle control and apoptosis. It is still unclear whether these isoforms have specialised biological functions and whether this specialisation is based on isoform-specific ligand binding, expression regulation or specific localisation. Therefore, we studied the subcellular distribution of 14-3-3 sigma and 14-3-3 zeta in vivo in various mammalian cell types using yellow fluorescent protein fusions and isoform-specific antibodies. 14-3-3 sigma was mainly localised in the cytoplasm and only low levels were present in the nucleus, whereas 14-3-3 zeta was found at relatively higher levels in the nucleus. Fluorescence recovery after photobleaching (FRAP) experiments indicated that the 14-3-3 proteins rapidly shuttle in and out of the nucleus through active transport and that the distinct subcellular distributions of 14-3-3 sigma and 14-3-3 zeta are caused by differences in nuclear export. 14-3-3 sigma had a 1.7x higher nuclear export rate constant than 14-3-3 zeta, while import rate constants were equal. The 14-3-3 proteins are exported from the nucleus at least in part by a Crm1-dependent, leptomycin B-sensitive mechanism. The differences in subcellular distribution of 14-3-3 that we found in this study are likely to reflect a molecular basis for isoform-specific biological specialisation.
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