CD36 Signaling via Srcfamily Kinases Modulates IRBC Adhesion

We have generated pharmacological and functional data that are consistent with a role for intracellular signaling and subsequent dephosphorylation of the CD36 ectodomain in mediating firm adhesion of IRBC under flow conditions. Specifically, we have demonstrated that the binding of PpMC-179 to CD36, as well as cross-linking CD36 with OKM5, activated the ERK 1/2 MAP kinase pathway in HDMEC that was dependent on Src-family kinase activity. The PpMC-179 peptide represents the functional binding domain of the parasite cytoadherent ligand PfEMP1 to CD36. Our finding is therefore the first direct demonstration that IRBC-CD36 interaction can in fact induce an intracel-lular signal in the host cells.

To determine the functional consequence of the intracel-lular activating, we treated HDMEC with PP1, a Src-family

Binding sites PfEMPI: 145-171 QKM5: 155-1B3 TSP-1; 139-155 & 9S-110

N-termlnus C-lemtnus

Figure 2 CD36 membrane topology and binding sites. This unique structure contains two cytoplasmic tails and two extracellular loops separated by a hydrophobic section that sits within the outer leaflet of the plasma membrane. Threonine-92 is phosphorylated in platelet CD36.

Figure 4 Proposed model of the regulation of IRBC adhesion to CD36 on microvascular endothelium under flow conditions. The initial attachment of IRBCs to CD36 (step 1) leads to a Src-family kinase-dependent intracellular signal (step 2) that is responsible for increasing subsequent IRBC adhesion to CD36 by means of an ecto-alkaline phosphatase (ecto-ALP) (step 3) that dephosphorylates and hence increases the binding affinity of CD36 for IRBCs (step 4). (From Yipp et al., 2003, with permission of The American Society of Hematology.)

Figure 4 Proposed model of the regulation of IRBC adhesion to CD36 on microvascular endothelium under flow conditions. The initial attachment of IRBCs to CD36 (step 1) leads to a Src-family kinase-dependent intracellular signal (step 2) that is responsible for increasing subsequent IRBC adhesion to CD36 by means of an ecto-alkaline phosphatase (ecto-ALP) (step 3) that dephosphorylates and hence increases the binding affinity of CD36 for IRBCs (step 4). (From Yipp et al., 2003, with permission of The American Society of Hematology.)

kinase selective inhibitor. PP1 inhibited adhesion of IRBCs to HDMEC monolayers in a flow chamber assay and to intact human microvessels in vivo in a human-SCID mouse model. The effect of PP1 could be mimicked by levamisole, a specific alkaline phosphatase inhibitor. Furthermore, firm adhesion to PPl-treated endothelium could be restored by the addition of exogenous alkaline phosphatase. Collectively, these results strongly support a novel mechanism for the modulation of cytoadherence under flow conditions through a signaling pathway involving CD36, Src-family kinases, and an ecto-alkaline phosphatase, most likely the GPI-anchored endothelial alkaline phosphatase. Based on these findings, we propose that the initial attachment of IRBCs to CD36 under flow conditions (step 1 in Figure 4) triggers a Src-family kinase-dependent intracellular signal (step 2) that is responsible for increasing subsequent adhesion of IRBCs to CD36 by means of an ecto-alkaline phosphatase (step 3). The enzyme dephosphorylates CD36, leading to a higher binding affinity of CD36 for IRBCs (step 4). Through this mechanism, a small number of strongly adherent IRBCs in a clinical parasite isolate can activate the endothelium and promote the adhesion of the majority of IRBCs.

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