Interaction of FK506-binding protein 13 with brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1): Effects of FK506

Padilla, Philip Ian; Chang, Min-ju; Pacheco–Rodriguez, Gustavo; Adamik, Ronald; Moss, Joel; Vaughan, Martha

doi:10.1073/pnas.2628047100

Cited by 34 publications

(27 citation statements)

References 36 publications

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“…As a proline isomerase located in an intracellular compartment dedicated to protein folding, it was logically inferred that FKBP13 likely plays a role as an ER-folding catalyst or molecular chaperone. Recently, FKBP13 has been identified to interact with brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1) by yeast 2-hybrid and confirmed by coimmunoprecipitation (Padilla et al 2003). Because BIG1 functions to activate adenosine 5Ј diphosphate-ribosylation factors, which are essential components of intracellular vesicular transport, this finding further supports a role for FKBP13 in the secretory process.…”

Section: Discussionmentioning

confidence: 80%

Developmental regulation and coordinate reexpression of FKBP65 with extracellular matrix proteins after lung injury suggest a specialized function for this endoplasmic reticulum immunophilin

et al. 2005

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FKBP65 (65-kDa FK506-binding protein) is an endoplasmic reticulum (ER)-localized peptidyl-prolyl cis-trans isomerase predicted to play a role in the folding and trafficking of secretory proteins. In previous studies, we have shown that FKBP65 is developmentally regulated and associates with the extracellular matrix protein, tropoelastin, during its maturation and transport through the ER. In this study, we show that FKBP65 is expressed in the lung with the same developmental pattern as tropoelastin and other matrix proteins. To test the hypothesis that FKBP65 is upregulated at times when extracellular matrix proteins are being actively synthesized and assembled, adult mice were treated with bleomycin to cause reinitiation of matrix protein production during the ensuing development of pulmonary fibrosis. After bleomycin instillation, FKBP65 expression was reactivated in the lung with a pattern similar to that observed for tropoelastin and type I collagen. Using human lung fibroblast cultures, we showed that FKBP65 does not undergo the unfolded protein response, a response associated with an upregulation of resident ER proteins that occurs after increased ER stress. When fibroblasts were treated with transforming growth factor (TGF)-␤1, which is upregulated during the development of pulmonary fibrosis and known to induce matrix production, FKBP65 expression and synthesis was also increased. Similar to type I collagen and tropoelastin, this response was completely inhibited in a dose-dependent manner by GGTI-298, a geranylgeranyl transferase I inhibitor. Treatment of fibroblasts with an inhibitor of ribonucleic acid (RNA) polymerase II after TGF-␤1 treatment showed that the effect of TGF-␤1 was not because of increased stabilization of the FKBP65 messenger RNA. In summary, we have shown that FKBP65 is highly expressed in lung development, downregulated in the adult, and can be reactivated in a coordinated manner with extracellular matrix proteins after lung injury. The expression pattern of FKBP65, which is atypical for general ER foldases, suggests that FKBP65 has a distinct set of developmentally regulated protein ligands. The response to injury, which may be in part a direct response to TGF-␤1, assures the presence of FKBP65 in the ER of cells actively producing components of the extracellular matrix.

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Section: Discussionmentioning

confidence: 80%

Developmental regulation and coordinate reexpression of FKBP65 with extracellular matrix proteins after lung injury suggest a specialized function for this endoplasmic reticulum immunophilin

et al. 2005

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“…Similarly to GNOM, the two mammalian large ARF-GEFs BIG1 and BIG2 interact with the immunophilin FKBP13 in Jurkat T cells via their conserved DCB domains (Padilla et al, 2003). Curiously, mammalian FKBP13 and Arabidopsis CYP19-4 harbor an N-terminal signal for translocation into the endoplasmic reticulum (ER) (Jin et al, 1991;Saito et al, 1999), whereas large ARF-GEFs are localized in the cytosol or to the cytosolic leaflet of target membranes (Shin and Nakayama, 2004).…”

Section: The Immunophilin Cyp19-4 Appears Not To Play a Role In Gnom mentioning

confidence: 99%

Membrane Association of theArabidopsisARF Exchange Factor GNOM Involves Interaction of Conserved Domains

et al. 2008

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The GNOM protein plays a fundamental role in Arabidopsis thaliana development by regulating endosome-to-plasma membrane trafficking required for polar localization of the auxin efflux carrier PIN1. GNOM is a family member of large ARF guanine nucleotide exchange factors (ARF-GEFs), which regulate vesicle formation by activating ARF GTPases on specific membranes in animals, plants, and fungi. However, apart from the catalytic exchange activity of the SEC7 domain, the functional significance of other conserved domains is virtually unknown. Here, we show that a distinct N-terminal domain of GNOM mediates dimerization and in addition interacts heterotypically with two other conserved domains in vivo. In contrast with N-terminal dimerization, the heterotypic interaction is essential for GNOM function, as mutations abolishing this interaction inactivate the GNOM protein and compromise its membrane association. Our results suggest a general model of large ARF-GEF function in which regulated changes in protein conformation control membrane association of the exchange factor and, thus, activation of ARFs.

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“…Elements identified later include a site in the N-terminal region that interacts with FK506-binding protein 13 (10) and an A kinase-anchoring protein sequence identical to one of three such sequences that differ in specificities for binding each of the four cAMP-dependent protein kinase regulatory (R) subunits and that were first identified in BIG2 (11), the very similar GEP initially co-purified with BIG1 (9). PKA-catalyzed phosphorylation of serine-883, a predicted substrate site in BIG1, was required for its cAMP-induced nuclear accumulation (8).…”

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confidence: 99%

Interaction of brefeldin A-inhibited guanine nucleotide-exchange protein (BIG) 1 and kinesin motor protein KIF21A

Shen

Meza-Carmen

Puxeddu

et al. 2008

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

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. These newly recognized interactions of BIG1 and KIF21A should enable us to understand better the mechanisms through which, acting together, they may integrate local events in membrane trafficking with longer-range transport processes and to relate those processes to the diverse signaling and scaffold functions of BIG1.ADP-ribosylation factor 1 ͉ Golgi ͉ microtubule B refeldin A-inhibited guanine nucleotide-exchange protein (BIG) 1, a member of the Sec7 family of ADP-ribosylation factor (ARF) guanine nucleotide-exchange proteins (GEP), activates class I ARFs (human ARF1 and 3) by catalyzing replacement of ARF-bound GDP with GTP, to initiate membrane vesicle formation (1-3). BIG1 had been localized at trans-Golgi structures (4, 5); by electron microscopy, Golgi membranes in BIG1-depleted cells were less sharply defined and had more vesicle-like structures at the trans face than those in control or BIG2 siRNA-treated cells (6). BIG1 also was found in nuclei of serum-deprived HepG2 cells or after their brief incubation with the immunosuppressive drug FK506 (7) or with cAMP (8).In the ϳ 200-kDa BIG1 molecule, a central ARF-activating Sec7 domain was the first recognized functional structure (9). Elements identified later include a site in the N-terminal region that interacts with FK506-binding protein 13 (10) and an A kinase-anchoring protein sequence identical to one of three such sequences that differ in specificities for binding each of the four cAMP-dependent protein kinase regulatory (R) subunits and that were first identified in BIG2 (11), the very similar GEP initially co-purified with BIG1 (9). PKA-catalyzed phosphorylation of serine-883, a predicted substrate site in BIG1, was required for its cAMP-induced nuclear accumulation (8). Later experiments with recombinant proteins in vitro demonstrated that GEP activity of BIG1 was decreased after phosphorylation by PKA (12). Most recently, it was reported that BIG1, nucleolin, U3 small nucleolar RNA, the U3-binding protein fibrillarin, and the RNA-binding protein La may exist together in nuclear complexes, consistent with a potential role for BIG1 in nucleolar function (13). The C-terminal region of BIG1 includes a binding site for myosin IXb. This motor protein possesses GTPaseactivating protein activity for Rho that is inhibited by competition with RhoA for binding to myosin IXb (14).A role for myosin IXb in the translocation of BIG1 along actin fibers in cells remains to be demonstrated. We present here evidence that BIG1 interacts directly with the motor protein KIF21A, which is involved in its microtubule-dependent transport. KIF21A is a member of the family of kinesin proteins that control cell morphogenesis, survival, and other functions (15). The 45 KIF molecules are classified according to position of the motor domain as N-terminal, middle, and C-terminal types, respectively, N-, M-, and C-kinesins (16). KIF21A is an N-kinesin that acts as a plus-end-directed motor to move cargo away from the microtubule-organizing center. BIG1 activation of ARF1 also ...

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Interaction of FK506-binding protein 13 with brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1): Effects of FK506

Cited by 34 publications

References 36 publications

Developmental regulation and coordinate reexpression of FKBP65 with extracellular matrix proteins after lung injury suggest a specialized function for this endoplasmic reticulum immunophilin

Developmental regulation and coordinate reexpression of FKBP65 with extracellular matrix proteins after lung injury suggest a specialized function for this endoplasmic reticulum immunophilin

Membrane Association of theArabidopsisARF Exchange Factor GNOM Involves Interaction of Conserved Domains

Interaction of brefeldin A-inhibited guanine nucleotide-exchange protein (BIG) 1 and kinesin motor protein KIF21A

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