Cho, Jae Youl; (2001) Molecular mechanism of CD98 function. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

CD98 is expressed on both haematopoietic and non-haematopoietic cells and has been implicated in a variety of different functional role in cell physiology and immunobiology such as amino acid transport, oncogenic transformation and cell adhesion and fusion. Little is known about molecular mechanism of CD98 function, including interaction with other molecules and signalling pathways induced by CD98 activation. The first study examined the functional interactions between CD98 and other adhesion molecules such as CD29 and CD 147 on the surface of the promonocyte line U937, using a quantitative assay of cell aggregation and blocking monoclonal antibodies to adhesion molecules. Two antibodies to CD147, an immunoglobulin superfamily member whose function has remained unclear, were also potent inhibitors of the aggregation induced via the ligation of both CD98 and CD29. CD98 blocking mAbs also diminished CD29-induced homotypic aggregation. The results suggest that CD98, CD29 and CD147 are functionally associated within a multi-molecular unit which regulates cell aggregation. To dissect signalling pathways induced by CD98 activation, CD98-mediated U937 homotypic aggregation was further carefully evaluated with pharmacological and biochemical approaches. CD98 ligation induced a selective membrane translocation of the novel PKCδ isoform, as an essential step in mediating U937 homotypic aggregation. CD98-induced PKCδ activation mediated activation of MAPK, ERKl/2 and p38, as well as tyrosine phosphorylation. Collectively, CD98 activation may be selectively linked to PKCδ activation. The CD98-induced aggregation was negatively regulated by PMA-responsive PKC isoforms because PKC inhibitors and activators enhanced or inhibited CD98-induced intercellular adhesion. PMA also induced the translocation of PKC α, β, and γ, suggesting that the PMA-responsive PKC isoforms were conventional isoforms of PKC. Together, these data provide strong evidence that PMA-responsive conventional PKC may play a key role in the negative regulation in CD98-induced signalling and homotypic aggregation.

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