Fibroblast Growth Factor Homologous Factors and the Islet Brain-2 Scaffold Protein Regulate Activation of a Stress-activated Protein Kinase

Schoorlemmer, Jon; Goldfarb, Mitchell

doi:10.1074/jbc.m205520200

Cited by 95 publications

(75 citation statements)

References 48 publications

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“…The binding of Tat to HSPG followed by low-density lipoprotein receptor-related protein (LPR)-mediated endocytosis is a pathway for the entry of Tat into neurons (37). Islet-brain 2 (IB2) is the only known molecule to which FGF12 can bind intracellularly, and it is expressed in the brain, pancreas, and specific cell lines (38,39). However, IB2 may not be a receptor for internalization because repression of IB2 did not affect the cellular uptake of FGF12 in a human mast cell line HMC-1 (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor-12 (FGF12) Translocation into Intestinal Epithelial Cells Is Dependent on a Novel Cell-penetrating Peptide Domain

Nakayama¹,

Yasuda²,

Umeda³

et al. 2011

Journal of Biological Chemistry

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The extracellular effect of fibroblast growth factor-12 (FGF12) remains unknown because FGF12 cannot activate any fibroblast growth factor receptors (FGFRs), and FGF12 is not currently thought to be released from cells. We reported previously that FGF12 plays an intracellular role in the inhibition of radiation-induced apoptosis. In this study, we demonstrated that recombinant FGF12 was able to be internalized into the cytoplasm of a rat intestinal epithelial cell line, IEC6, and this process was dependent on two novel cell-penetrating peptide (CPP) domains (CPP-M and CPP-C). In particular, CPP-C, composed of ϳ10 amino acids, was identified as a specific domain of FGF12 and its subfamily in the C-terminal region (residues 140 -149), although CPP-M was a common domain in the internal region of the FGF family. The absence of CPP-C from FGF12 or a mutation (E142L) in the CPP-C domain drastically reduced the internalization of FGF12 into cells. Therefore, CPP-C played an essential role in the internalization of FGF12. In addition, CPP-C was able to deliver other polypeptides into cells as a CPP because an FGF1/CPP-C chimeric protein was internalized into IEC6 cells more efficiently than wild-type FGF1. Finally, intraperitoneally added FGF12 inhibited radiation-induced apoptosis in the intestinal epithelial cells of BALB/c mice, and deletion of the CPP-C domain decreased the inhibition of the apoptosis. These findings suggest that exogenous FGF12 can play a role in tissues by translocating into cells through the plasma membrane, and the availability of this novel CPP provides a new tool for the intracellular delivery of bioactive molecules.

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Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor-12 (FGF12) Translocation into Intestinal Epithelial Cells Is Dependent on a Novel Cell-penetrating Peptide Domain

Nakayama¹,

Yasuda²,

Umeda³

et al. 2011

Journal of Biological Chemistry

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“…The subcellular distribution of endogenous neuronal FHF2 isoforms, as studied on Western blots of fractionated tissues, does not readily comply with observations made on transfected cells. FHF2a and FHF2b are both detected abundantly in postnuclear fractions of brain homogenates (Schoorlemmer and Goldfarb, 2002). For both FHF2 isoforms, some of the protein is detected in plasma membranes purified by lectin affinity partitioning, while some of the protein is in the free cytosol, detected in the supernatant after high-speed membrane pelleting (M. Goldfarb, unpublished data).…”

Section: Vertebrate Fhf Gene Expression and Protein Distributionmentioning

confidence: 98%

Fibroblast growth factor homologous factors: Evolution, structure, and function

Goldfarb¹

2005

Cytokine & Growth Factor Reviews

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198

175

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SummaryFibroblast growth factor homologous factors (FHFs) bear strong sequence and structural similarity to fibroblast growth factors (FGFs). However, the biochemical and functional properties of FHFs are largely, if not totally, unrelated to those of FGFs. Whereas FGFs function through binding to the extracellular domains of FGF receptors (FGFRs), FHFs bind to intracellular domains of voltage-gated sodium channels (VGSCs) and to a neuronal MAP kinase scaffold protein, isletbrain-2 (IB2). These findings demonstrate the remarkable functional adaptability during evolution of the FGF gene family. FHF gene mutations in mice result in a range of neurological abnormalities, and at least one of these anomalies, cerebellar ataxia, is linked to FHF mutations in humans. This article reviews the sequences and structure of FHFs, along with our still limited understanding of FHF function.

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“…30,31 However, there are relatively few known p38MAPK scaffolds, with JIP2 and JIP4 reported to bind to and possibly regulate localisation of p38MAPK activity. [32][33][34] Osmosensing scaffold for MEKK3 (OSM) has also been shown to act as a p38MAPK scaffold. 35 OSM responds to osmotic stress by recruiting p38MAPK and Rac to membrane ruffles, wherein they co-operate to reorganise the actin cytoskeleton.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis commitment and activation of mitochondrial Bax during anoikis is regulated by p38MAPK

et al. 2009

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Most cells undergo apoptosis through the intrinsic pathway. This is dependent on mitochondrial outer membrane permeabilisation (MOMP), which is mediated by the pro-apoptotic Bcl-2 family proteins, Bax and Bak. During apoptosis, Bax translocates from the cytosol to the outer mitochondrial membrane (OMM), wherein it contributes to the formation of pores to release cytochrome-c. However, it remains unclear whether Bax translocation is sufficient to bring about MOMP or whether Bax requires further signals on the OMM to be fully activated. We have previously shown that during mammary epithelial cell anoikis, Bax translocation does not commit cells to MOMP and detached cells are rescued if survival signals from the extracellular matrix (ECM) are restored. These findings implied that a second signal is required for mitochondrial Bax to fully activate and cause MOMP. We now identify p38MAPK (mitogen-activated protein kinase) as this necessary signal to activate Bax after its translocation to mitochondria. The inhibition of p38MAPK did not prevent Bax translocation, but its activity was required for mitochondrial Bax to bring about MOMP. p38MAPK was activated and recruited to a high molecular weight mitochondrial complex after loss of ECM attachment. Artificially targeting p38MAPK to the OMM increased the kinetics of anoikis, supporting a requirement for its mitochondrial localisation to regulate Bax activation and drive commitment to apoptosis. Metazoan cells are pre-programmed to undergo apoptosis in response to becoming damaged or losing essential survival signals. Apoptosis in response to these cellular stresses is initiated through the intrinsic, or mitochondrial, pathway. 1 During intrinsic apoptosis, mitochondrial outer membrane permeabilisation (MOMP) results in the release of proteins, such as cytochrome-c and second mitochondrial activator of caspases (Smac)/Diablo, which activate the caspases to drive cell death. The release of cytochrome-c and Smac/Diablo is an extremely rapid event, with mitochondria throughout the cell releasing their contents within a few minutes of MOMP first commencing. 2,3 The resulting activation of caspases occurs immediately and cell death is complete within a few minutes. After MOMP, cells rapidly lose viability, even if caspase activation is inhibited. Thus, MOMP represents a point at which cells cannot be rescued from an apoptotic fate.The Bcl-2 family of proteins regulates MOMP. 4 These are characterised by a number of shared regions of sequence homology, the Bcl-2 Homology (BH) domains. Pro-survival members, such as Bcl-2 and Bcl-X L , share BH-domains 1-4. In contrast, the pro-apoptotic proteins, Bax and Bak, only posses BH-domains 1, 2 and 3. A third group of Bcl-2 proteins are the BH3-only proteins, which function by sensing survival and stress signals, and transmit these to the pro-and antiapoptotic multi-domain proteins. 5 The multi-domain proapoptotic proteins, Bax and Bak, are expressed in virtually all tissues, and are absolutely required for MOMP to occur. 6 Cells deriv...

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Fibroblast Growth Factor Homologous Factors and the Islet Brain-2 Scaffold Protein Regulate Activation of a Stress-activated Protein Kinase

Cited by 95 publications

References 48 publications

Fibroblast Growth Factor-12 (FGF12) Translocation into Intestinal Epithelial Cells Is Dependent on a Novel Cell-penetrating Peptide Domain

Fibroblast Growth Factor-12 (FGF12) Translocation into Intestinal Epithelial Cells Is Dependent on a Novel Cell-penetrating Peptide Domain

Fibroblast growth factor homologous factors: Evolution, structure, and function

Apoptosis commitment and activation of mitochondrial Bax during anoikis is regulated by p38MAPK

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