A novel PKC-regulated mechanism controls CD44–ezrin association and directional cell motility

Legg, James; Lewis, Clive J.; Parsons, Maddy; Ng, Tony; Isacke, Clare M.

doi:10.1038/ncb797

Cited by 219 publications

(170 citation statements)

References 47 publications

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“…As previously reported (Legg et al, 2002), phorbol ester treatment resulted in de-phosphorylation at Ser325. In contrast, the level of Ser325 phosphorylation remained unchanged in Bt 2 cAMP-treated cells.…”

Section: Resultssupporting

confidence: 85%

“…However, although PKA can phosphorylate Ser316 in vitro (Figure 2b), no Ser316 phosphorylation is observed in a PKC in vitro kinase assay (Legg et al, 2002). To better delineate the mechanism of Ser316 phosphorylation, both time-course and inhibitor experiments were undertaken.…”

Section: Cd44-dependent Chemotaxis Towards Phorbol Estersmentioning

confidence: 99%

“…CD44 has been implicated in modulating cellular responses to PMA (Legg et al, 2002;Nagano et al, 2004;Cichy et al, 2005) and phosphorylation events occurring in the cytoplasmic tail of CD44 have been shown to modulate the chemotactic response towards PMA (Legg et al, 2002). In resting cells, CD44 is constitutively phosphorylated to high stoichiometry (up to 40%) on a single serine residue, Ser325 (Neame and Isacke, 1992;Pure et al, 1995;Peck and Isacke, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…Initially, it was demonstrated that CD44 can be phosphorylated in vitro by PKC (Kalomiris and Bourguignon, 1989) but 32 P-orthophosphate labelling of PMA-treated cells revealed no change in overall CD44 phosphorylation levels (Camp et al, 1991;Neame and Isacke, 1992). These contradictory observations were resolved when it was demonstrated that PMA treatment results in a complete de-phosphorylation of CD44 at Ser325 and concomitant phosphorylation at one or more other serine residues (Legg et al, 2002). Ser291, which lies in a consensus PKC phosphorylation sequence, was the only CD44 cytoplasmic tail serine shown to be phosphorylated by PKC in vitro (Lewis et al, 2001;Legg et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…These contradictory observations were resolved when it was demonstrated that PMA treatment results in a complete de-phosphorylation of CD44 at Ser325 and concomitant phosphorylation at one or more other serine residues (Legg et al, 2002). Ser291, which lies in a consensus PKC phosphorylation sequence, was the only CD44 cytoplasmic tail serine shown to be phosphorylated by PKC in vitro (Lewis et al, 2001;Legg et al, 2002). However, these studies did not investigate whether Ser291 is the sole site of CD44 phosphorylation in vivo.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Directional sensing of a phorbol ester gradient requires CD44 and is regulated by CD44 phosphorylation

2006

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Cancer progression is associated with enhanced directional cell migration, both of the tumour cells invading into the stroma and stromal cells infiltrating the tumour site. In cell-based assays to study directional cell migration, phorbol esters are frequently used as a chemotactic agent. However, the molecular mechanism by which these activators of protein kinase C (PKC) result in the establishment of a polarized migratory phenotype is not known. Here we show that CD44 expression is essential for chemotaxis towards a phorbol ester gradient. In an investigation of CD44 phosphorylation kinetics in resting and stimulated cells, Ser316 was identified as a novel site of phosphorylation following activation of PKC. PKC does not phosphorylate Ser316 directly, but rather mediates the activation of downstream Ser316 kinase(s). In transfection studies, a phosphorylation-deficient Ser316 mutant was shown to act in a dominant-negative fashion to impair chemotaxis mediated by endogenous CD44 in response to a phorbol ester gradient. Importantly, this mutation had no effect on random cell motility or the ability of cells to migrate directionally towards a cocktail of chemoattractants. These studies demonstrate that CD44 functions to provide directional cues to migrating cells without affecting the motility apparatus.

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Section: Resultssupporting

confidence: 85%

Section: Cd44-dependent Chemotaxis Towards Phorbol Estersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Directional sensing of a phorbol ester gradient requires CD44 and is regulated by CD44 phosphorylation

2006

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Receptor‐Targeted Drug Delivery and the (Many) Problems We Know of: The Case of CD44 and Hyaluronic Acid

rosa

Tirelli

2018

Adv. Biosys.

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CD44 is best known for being the most common receptor of hyaluronic acid (HA). It is also a heterogeneous molecule: while its standard isoform (CD44s) is ubiquitously expressed, there are also a range of variants (CD44v), and both CD44s and CD44v undergo a variety of post‐translational modifications. The signaling roles and frequent overexpression of both CD44s and CD44v in cancer (e.g., in cancer initiating cells/cancer stem cells) has raised interest in them for diagnostic applications, but also—and most importantly for this review—as possible molecular targets in tumor therapy, with their endocytic character being a clear advantage for the intracellular release of payloads. In this area, the most popular approach employs HA‐based carriers. However, their rational design and therefore the success of HA‐based therapies are hampered by the rather limited understanding of not only the identity, but also the dynamic properties of CD44. In this review, the reader is exposed to the full breadth of the challenges that HA carriers currently face, which start at the CD44 post‐transcriptional and post‐translational heterogeneity, and also include the understanding of receptor clustering phenomena (influencing also HA avidity), as well as the evaluation of off‐target effects.

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Glioblastoma Spheroid Invasion through Soft, Brain‐Like Matrices Depends on Hyaluronic Acid–CD44 Interactions

Safarians

Sohrabi

Solomon

et al. 2023

Adv Healthcare Materials

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Increased secretion of hyaluronic acid (HA), a glycosaminoglycan abundant in the brain extracellular matrix (ECM), correlates with worse clinical outcomes for glioblastoma (GBM) patients. GBM cells aggressively invade the brain parenchyma while encountering spatiotemporal changes in their local ECM, including HA concentration. To investigate how varying HA concentrations affect GBM invasion, patient‐derived GBM cells are cultured within a soft, 3D matrix in which HA concentration is precisely varied and cell migration observed. Data demonstrate that HA concentration can determine the invasive activity of patient‐derived GBM cells in a biphasic and highly sensitive manner, where the absolute concentration of HA at which cell migration peaked is specific to each patient‐derived line. Furthermore, evidence that this response relies on phosphorylated ezrin, which interacts with the intracellular domain of HA‐engaged CD44 to effectively link the actin cytoskeleton to the local ECM is provided. Overall, this study highlights CD44–HA binding as a major mediator of GBM cell migration that acts independently of integrins and focal adhesion complexes and suggests that targeting HA–CD44–ezrin interactions represents a promising therapeutic strategy to prevent tumor cell invasion in the brain.

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A novel PKC-regulated mechanism controls CD44–ezrin association and directional cell motility

Cited by 219 publications

References 47 publications

Directional sensing of a phorbol ester gradient requires CD44 and is regulated by CD44 phosphorylation

Directional sensing of a phorbol ester gradient requires CD44 and is regulated by CD44 phosphorylation

Receptor‐Targeted Drug Delivery and the (Many) Problems We Know of: The Case of CD44 and Hyaluronic Acid

Glioblastoma Spheroid Invasion through Soft, Brain‐Like Matrices Depends on Hyaluronic Acid–CD44 Interactions

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