Title

Heparan sulfate proteoglycan and FGF receptor target basic FGF to different intracellular destinations

Document Type

Article

Publication Date

1-1-1993

Abstract

Basic FGF is a prototype of a family of heparin binding growth factors that regulate a variety of cellular responses including cell growth, morphogenesis and differentiation. At least two families of receptors bind bFGF and could mediate its response: (1) tyrosine kinase-containing FGF receptors, designated FGFR-1 to FGFR-4, and (2) heparan sulfate proteoglycans that bind bFGF through their heparan sulfate chains. Both are known to undergo internalization and thus bFGF bound to the different receptors may be internalized via more than one pathway. It is not known whether the intracellular fate of bFGF differs depending upon which receptor binds it at the cell surface. To investigate the respective roles of these receptors in the intracellular targeting of bFGF, we utilized NMuMG cells that bind and internalize bFGF through their heparan sulfate proteoglycans, but do not express detectable levels of FGFRs nor respond to bFGF. Basic FGF conjugated to saporin (bFGF-saporin) was used as a probe to study targeting of bFGF by the different receptors. Saporin is a cytotoxin that has no effect on cells if added exogenously. However, it kills cells if it gains access to the cytoplasm. The NMuMG cells internalize bFGF-saporin but are not killed. Transfecting these cells with FGFR-1 results in bFGF-responsive cells, which bind and internalize bFGF through FGFR-1, and are killed. Removing the heparan sulfate from these cells eliminates killing by bFGF-saporin. Therefore, endocytosis of bFGF-saporin by these receptors can lead to two fates: (i) bFGF-saporin internalized by heparan sulfate proteoglycan, which is not targeted to the cytoplasm, and (ii) a bFGF-saporin internalized by the bFGF-saporin bound to a complex of heparan sulfate proteoglycan and FGFR-1 from which the saporin can gain access to the cytoplasm.

Publication Source (Journal or Book title)

Journal of Cell Science

First Page

1085

Last Page

1093

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