Phorbol 12-Myristate 13-Acetate-Induced Release of the Colony-Stimulating Factor 1 Receptor Cytoplasmic Domain into the Cytosol Involves Two Separate Cleavage Events

Wilhelmsen, Kevin; Geer, Peter van der

doi:10.1128/mcb.24.1.454-464.2004

Cited by 74 publications

(67 citation statements)

References 85 publications

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“…The soluble fraction was concentrated and analyzed for the presence of the cleaved cytoplasmic domain. As can be seen in Figure 6A, in the presence of DN-PS1, although, in accord with previous studies (Wilhelmsen and van der Geer, 2004), we did not detect a massive accumulation of the uncleaved membranal protein, very little of the CD74-ICD was released into the cytosol. To further follow the involvement of presenilin in CD74 intramembrane cleavage, we used the ␥-secretase/PS1 specific inhibitor, DAPT (WO 9822494).…”

Section: The I-clip Involved In Cd74 Intramembrane Cleavagesupporting

confidence: 75%

CD74 Is a Member of the Regulated Intramembrane Proteolysis-processed Protein Family

Becker-Herman

Arie

Medvedovsky

et al. 2005

MBoC

118

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Quite a few regulatory proteins, including transcription factors, are normally maintained in a dormant state to be activated after internal or environmental cues. Recently, a novel strategy, requiring proteolytic cleavage, was described for the mobilization of dormant transcription factors. These transcription factors are initially synthesized in an inactive form, whereas "nesting" in integral membrane precursor proteins. After a cleavage event, these new active factors are released from the membrane and can migrate into the nucleus to drive regulated gene transcription. This mechanism, regulated intramembrane proteolysis (RIP), controls diverse biological processes in prokaryotes and eukaryotes in response to a variety of signals. The MHC class II chaperone, CD74 (invariant chain, Ii), was previously shown to function as a signaling molecule in several pathways. Recently, we demonstrated that after intramembranal cleavage, the CD74 cytosolic fragment (CD74-ICD) is released and induces activation of transcription mediated by the NF-B p65/RelA homodimer and the B-cell-enriched coactivator, TAF II 105. Here, we add CD74 to the growing family of RIP-processed proteins. Our studies show that CD74 ectodomain must be processed in the endocytic compartments to allow its intramembrane cleavage that liberates CD74 intracellular domain (CD74-ICD). We demonstrate that CD74-ICD translocates to the nucleus and induces the activation of the p65 member of NF-B in this compartment. INTRODUCTIONQuite a few regulatory proteins, including transcription factors, are normally maintained in a dormant state and are activated by internal or environmental cues. Recently, a novel strategy (regulated intramembrane proteolysis [RIP]), based on proteolytic cleavage, was discovered for the mobilization of dormant transcription factors. These transcription factors are synthesized initially as inactive, membranebound precursors. Once triggered, RIP proteins are cleaved within the plane of the membrane, and their cytosolic fragment migrates into the nucleus to drive transcription.In general, in most RIP cases reported, cleavage proceeds through a two-step sequential proteolytic process. The first step involves the cleavage of the extracytoplasmic segment to shorten the ectodomain to Ͻ30 aa. This seems to be a requirement for the second proteolytic event, which occurs at the transmembrane domain. The initial shedding prepares the substrate for the intramembrane proteolysis such that the transmembrane region becomes accessible to the second protease, which then releases the product from the lipid bilayer. The released cytosolic fragment then migrates into the nucleus. Intramembrane cleaving proteases (I-CLiPs) catalyze peptide bond hydrolysis in the plane of cellular membranes. These proteases are thought to mediate RIP (Brown et al., 2000), and the reactions they catalyze are, in most cases, part of highly controlled processes. The family of I-CLiPs is growing, and at present, three distinct protease families have been shown to catalyze intramem...

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Section: The I-clip Involved In Cd74 Intramembrane Cleavagesupporting

confidence: 75%

CD74 Is a Member of the Regulated Intramembrane Proteolysis-processed Protein Family

Becker-Herman

Arie

Medvedovsky

et al. 2005

MBoC

118

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“…Secretase cleavage of the colony-stimulating factor-1 receptor (CSF-1R) can be stimulated by CSF-1, LPS, or TPA (Wilhelmsen and van der Geer 2004;van der Geer 2007, 2008). Lipopolysaccharide (LPS) is a ligand for the Toll4 receptor and agonists for other Toll-like receptors also stimulate cleavage of CSF-1R.…”

Section: Colony Stimulating Factor-1 Receptormentioning

confidence: 99%

Receptor Tyrosine Kinases in the Nucleus

Carpenter

Liao

2013

Cold Spring Harbor Perspectives in Biology

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To date, 18 distinct receptor tyrosine kinases (RTKs) are reported to be trafficked from the cell surface to the nucleus in response to ligand binding or heterologous agonist exposure. In most cases, an intracellular domain (ICD) fragment of the receptor is generated at the cell surface and translocated to the nucleus, whereas for a few others the intact receptor is translocated to the nucleus. ICD fragments are generated by several mechanisms, including proteolysis, internal translation initiation, and messenger RNA (mRNA) splicing. The most prevalent mechanism is intramembrane cleavage by g-secretase. In some cases, more than one mechanism has been reported for the nuclear localization of a specific RTK. The generation and use of RTK ICD fragments to directly communicate with the nucleus and influence gene expression parallels the production of ICD fragments by a number of non-RTK cell-surface molecules that also influence cell proliferation. This review will be focused on the individual RTKs and to a lesser extent on other growth-related cell-surface transmembrane proteins.

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“…The generation of Ryk-ICD is required for Wnt3-dependent differentiation of the primary culture of neuronal progenitor cells, showing that PS-RIP of Ryk represents an efficient mechanism of signalling required for neuronal determination (Lyu et al, 2008). Other PS-RIP-dependent fragments of RTK have been observed in the nucleus, suggesting that the proteolytic cleavage could give these receptors the gift of ubiquity (Kasuga et al, 2007;Wilhelmsen and van der Geer, 2004).…”

Section: Rtk Cleavages F Ancot Et Almentioning

confidence: 99%

“…As evidenced, for instance, for CSF-R, IGF-IR, Tie1, EphB2 and Met the ICD is rapidly degraded through a proteasome-dependent mechanism (Wilhelmsen and van der Geer, 2004;Litterst et al, 2007;Marron et al, 2007;McElroy et al, 2007;Foveau et al, 2009) (Figure 2). Moreover, PS-RIP shares common features with the liganddependent degradation described for RTK, including endocytosis and ubiquitination.…”

Section: Downregulation Of Rtk By Presenilin-dependent Regulated Intrmentioning

confidence: 99%

Proteolytic cleavages give receptor tyrosine kinases the gift of ubiquity

et al. 2009

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Receptor tyrosine kinases (RTK) constitute a large family of membrane receptors which, in response to their respective ligand, transmit information into cells. RTK regulate multiple biological responses, and their deregulation is often associated with tumourigenesis. The intracellular signalling pathways initiated by full-length membrane RTK are studied extensively, but many RTK fragments showing unexpected cellular localization have been observed. These fragments are generated by proteolytic cleavages, catalyzed notably by caspases, membrane metalloproteases or g-secretase. Interestingly, these cleavages, in addition to regulating membrane receptor levels, generate active fragments that can regulate biological processes, such as transcription or the survival/apoptosis balance. Thus, proteolytic cleavages release RTK from the membrane and extend their functions. Furthermore, the RTK proteolysis are involved in regulating cell transformation, which highlights their potential as attractive targets for therapeutic strategies. Keywords: receptor tyrosine kinase; cleavages; caspase; metalloprotease; g-secretase; signalling RTK as a membrane mediator between the extracellular and intracellular compartmentsIn multicellular organisms, the dialogue between cells is crucial to harmonious development and, in adults, to tissue homeostasis. This dialogue operates notably through soluble cytokines and their cognate membrane receptors. Cytokines secreted by cells into the extracellular environment can bind with high affinity to the extracellular domains of their respective specific membrane receptors expressed on the surface of target cells. Ligand binding triggers activation of the receptor, which transmits the information from the extracellular to the intracellular compartment. Receptor tyrosine kinases (RTK) constitute a large family of information-transmitting membrane receptors. The variability of their extracellular regions results in a wide specificity range as regards cytokine ligands. Inversely, their intracellular regions possess a conserved tyrosine kinase domain, involved in message transmission (Hubbard and Till, 2000). Ligand-activated RTK can initiate multiple biological responses, including proliferation, cell motility, survival and differentiation.Receptor tyrosine kinases are activated through dimerization and trans-autophosphorylation of tyrosine residues. The intracellular region of an RTK then becomes a signalling platform that can recruit numerous cytoplasmic proteins through phosphorylated tyrosine residues. In turn, these signalling proteins activate signalling pathways commonly organized in a cascade, which will propagate the information inside the cell (Schlessinger, 2000). The signalling cascades are often interconnected and are able to activate or downregulate each other (Amit et al., 2007). Therefore, the entire intracellular signalling mechanism is viewed as a network rather than as a superposition of multiple linear pathways.In keeping with the involvement of RTK in controlling a wide range of bi...

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Phorbol 12-Myristate 13-Acetate-Induced Release of the Colony-Stimulating Factor 1 Receptor Cytoplasmic Domain into the Cytosol Involves Two Separate Cleavage Events

Cited by 74 publications

References 85 publications

CD74 Is a Member of the Regulated Intramembrane Proteolysis-processed Protein Family

CD74 Is a Member of the Regulated Intramembrane Proteolysis-processed Protein Family

Receptor Tyrosine Kinases in the Nucleus

Proteolytic cleavages give receptor tyrosine kinases the gift of ubiquity

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