An autocrine role for urokinase in phorbol ester-mediated differentiation of myeloid cell lines.

Nusrat, Asma; Chapman, Harold A.

doi:10.1172/jci115070

Cited by 130 publications

(94 citation statements)

References 53 publications

(46 reference statements)

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“…Importantly, the acquisition of the adherent phenotype is allegedly dependent on up-regulation of both uPA and uPAR, leading to increased surface densities of the corresponding uPA-uPAR complexes (44,45). Accordingly, we chose to stimulate these three monocytic cell lines with 100 nM PMA before plating them on vitronectin-coated coverslips in the presence or absence of 10 nM pro-uPA S356A and 100 nM anti-uPAR mAbs representing the various epitope bins.…”

Section: Resultsmentioning

confidence: 99%

Conformational Regulation of Urokinase Receptor Function

Gårdsvoll

Jacobsen

Kriegbaum

et al. 2011

Journal of Biological Chemistry

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The urokinase-type plasminogen activator receptor (uPAR) is a glycolipid-anchored membrane protein with an established role in focalizing uPA-mediated plasminogen activation on cell surfaces. Distinct from this function, uPAR also modulates cell adhesion and migration on vitronectin-rich matrices. Although uPA and vitronectin engage structurally distinct binding sites on uPAR, they nonetheless cooperate functionally, as uPA binding potentiates uPAR-dependent induction of lamellipodia on vitronectin matrices. We now present data advancing the possibility that it is the burial of the ␤-hairpin in uPA per se into the hydrophobic ligand binding cavity of uPAR that modulates the function of this receptor. Based on these data, we now propose a model in which the inherent interdomain mobility in uPAR plays a major role in modulating its function. Particularly one uPAR conformation, which is stabilized by engagement of the ␤-hairpin in uPA, favors the proper assembly of an active, compact receptor structure that stimulates lamellipodia induction on vitronectin. This molecular model has wide implications for drug development targeting uPAR function.Timely controlled cell migration is a decisive factor for a plethora of important biological processes that occur during development and adulthood. Controlled cell migration is thus intimately involved in both maintenance and dynamic remodeling of tissue architectures during, e.g. wound healing and mammary gland development (1). These processes are executed and tightly regulated via a complicated cross-talk between specific cell surface receptors (e.g. integrins) and insoluble protein components deposited in the extracellular matrix. The extracellular matrix is nonetheless thought to play a dual role in regulating cell migration, as it provides both the focal adhesion sites required for cellular traction and opposes migration by generating physical barriers (2, 3). Cell migration in vivo, therefore, requires a coordinated regulation of extracellular matrix proteolysis, adhesion, and signaling (4). The urokinase-type plasminogen activator receptor (uPAR) 2 may allegedly assist a rendezvous between these functions, as it has the potential to exert control at all three levels. Besides being responsible for focalizing uPA-mediated plasminogen activation on cell surfaces (5-7), uPAR also facilitates adherence to vitronectin embedded in the extracellular matrix (8 -10), and as a consequence, it promotes intracellular signaling (4, 11).The glycolipid-anchored uPAR is a modular glycoprotein composed of three homologous Ly6/uPAR-type (LU) protein domain repeats (5, 12). The far majority of proteins belonging to this domain family contain only a single copy of the LU module, as exemplified by the glycolipid-anchored CD59, the extracellular ligand binding domain in the TGF-␤ receptors, and the diverse group of secreted snake venom ␣-neurotoxins (13). In the human genome, five genes are recognized so far to encode proteins with multiple LU domains, and these are all confined to a small ...

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Section: Resultsmentioning

confidence: 99%

Conformational Regulation of Urokinase Receptor Function

Gårdsvoll

Jacobsen

Kriegbaum

et al. 2011

Journal of Biological Chemistry

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“…NB4 cells with onzin infection expressed higher level of onzin protein, and the ectopically expressed onzin protein could sufficiently overcome the decrease of endogenous onzin protein induced by PMA (Figure 4a (Figures 4b and c). Moreover, when treated with PMA for 24 h, empty vector-infected NB4 cells extended multiple podia and adhered onto culture dish plates (a hallmark of monocytic differentiation 14 ), which was significantly inhibited by onzin overexpression (Figure 4d). However, the effect of onzin overexpression on ATRA-induced granulocytic differentiation in NB4 cells is relative subtle, as assessed by CD11b/CD14-positive cells percentage, NBT reduction and morphology as well (Supplementary Figure S7B-D).…”

Section: Onzin Is a Negative Regulator For Pma-induced Differentiatiomentioning

confidence: 99%

The downregulation of onzin expression by PKCɛ-ERK2 signaling and its potential role in AML cell differentiation

Huang

Hou

et al. 2010

Leukemia

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Onzin is a small, novel, and highly conserved protein with unique structure and tissue-restricted expression. The regulation of its expression and biological roles remain greatly elusive. Here, we provide the first demonstration that onzin expression is significantly downregulated during differentiation induction of acute myeloid leukemic (AML) cell lines and primary cells by all-trans retinoic acid (ATRA) and especially by phorbol 12-myristate 13-acetate (PMA). Applying chemical inhibitions, RNA interferences, and transfected expressions of dominant negative mutants or constitutive catalytic forms of the related kinases, we show that protein kinase C-e (PKCe)-extracellular signal-regulated protein kinase 2 (ERK2) signaling axis is required for PMA-induced downregulation of onzin expression. The ectopic expression of onzin partially inhibits PMA-induced monocytic differentiation of AML cells, whereas suppression of onzin by specific short hairpin RNAs enhances PMA-induced differentiation to a degree. Furthermore, onzin partially inhibits the transcriptional activity of hematopoiesisrelated important transcription factor PU.1 via their interaction. Taken together, our results show that PMA downregulates onzin expression through PKCe-ERK2 signaling pathway, which favors monocytic differentiation of leukemic cells.

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“…The mature protein consists of three homologous cysteine-rich domains, the first of which comprises the u-PA binding domain (10). The receptor binds both single-chain and two-chain u-PA without inactivation, thus concentrating plasmin generation at the cell surface (2); it may be involved in internalization of u-PA/inhibitor complexes (5,11,12) and in signal transduction (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%