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Platelet Aggregation in Cancer

Platelet aggregation is a mechanism commonly used by the body to stop bleeding at the site of a wound. However, an increasing amount of evidence also indicates that platelet aggregation is involved in cancer metastasis and/or progression. Podoplanin is a transmembrane sialoglycoprotein that is found on the surface of cancer cells and is believed to be involved in tumor cell-induced platelet aggregation, tumor metastasis, and lymphatic vessel formation.

In this Paper of the Week, Katsue Suzuki-Inoue and colleagues have identified the receptor for podoplanin. They determined that the sialoglycoprotein interacts with C-type lectin-like receptor 2 (CLEC-2), a recently discovered receptor on the platelet membrane. They found that recombinant CLEC-2 inhibits platelet aggregation induced by podoplanin-expressing tumor cells or lymphatic endothelial cells, suggesting that the receptor is responsible for podoplanin-induced platelet aggregation. These findings indicate that podoplanin-induced platelet activation through CLEC-2 is one of the mechanisms of tumor metastasis, and suggest that inhibiting interactions between the two molecules may be a potential therapeutic target.

FOOTNOTES

See referenced article, J. Biol. Chem. 2007, 282, 25993-26001

To Die or Not to Die

The extracellular signal-regulated kinase (ERK) cascade is involved in cellular responses to survival, proliferative, and differentiative cues. The cascade is composed of Raf, MEK, and ERK kinases, which transmit signals directly between themselves via phosphorylation. However, recent studies have shown that the scaffolding protein, kinase suppressor of Ras 1 (KSR1), associates with the core components of the ERK cascade and is involved in regulating the cascade's timing, location, strength, and duration. KSR1 interacts constitutively with MEK and coordinates the assembly of a multiprotein complex that colocalizes MEK with its upstream activator Raf and downstream substrate ERK, thus facilitating the phosphorylation reactions required for ERK activation.

KSR1 is cleaved in apoptotic cells.

In this Paper of the Week, Melissa M. McKay and Deborah K. Morrison report that in response to multiple apoptotic stimuli, KSR1 undergoes caspase-dependent cleavage in apoptotic cells. This cleavage destroys the scaffolding function of the KSR1 protein and generates a stable C-terminal fragment that can inhibit ERK activation, thus inhibiting the anti-apoptotic action of KSR1. This paper demonstrates a novel role for KSR1 as a prosurvival signal and also a novel form of regulation by a scaffold protein.

FOOTNOTES

See referenced article, J. Biol. Chem. 2007, 282, 26225-26234

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