Inhibition of phosphatidylinositol 4-phosphate kinase by heparin. A possible mechanism for the antiproliferative effects of heparin

C. D. Smith, D. Wen, Susan L Mooberry, K. J. Chang

Research output: Contribution to journalArticle

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Abstract

Heparin and related glycosaminoglycans are important modulators of vascular smooth muscle cell growth, and may be involved in pathological processes such as atherosclerosis. Since polyphosphoinositide metabolism is a major mechanism for regulating cellular activities. including proliferation, the effects of glycosaminoglycans and polyanionic compounds on the activities of phosphoinositide kinases were characterized. Heparin and heparan sulphate caused dose-dependent inhibitions of rat brain cytosolic phosphatidylinositol 4-phosphate (PIP) kinase activity, with half-maximal inhibitory concentrations of approx. 0.5 and 5 μm respectively. PIP kinase was also inhibited by several dextran sulphates, but was not sensitive to inhibition by keratin sulphate, chondroitin sulphate or hyaluronic acid. Polynucleotides and acidic polypeptides were only weakly inhibitory. Heparin did not alter either the PIP- or the Mg2+-dependence of PIP kinase. Addition of heparin to brain membranes suppressed PIP kinase activity without affecting phosphatidylinositol (PI) kinase activity. Heparin interfered with the ability of a GTP analogue to stimulate PIP kinase activity in these membranes, suggesting that it uncouples the kinase from an activating guanine-nucleotide-binding protein. In cultured A-10 vascular smooth muscle cells, heparin caused dose- and time-dependent inhibition of [3H]thymidine incorporation into DNA. Similar treatments with heparin decreased cellular levels of phosphatidylinositol 4,5-bisphosphate (PIP2) without changing PI and PIP levels. Therefore heparin-mediated inhibition of PIP kinase appears to lead to decreases in PIP2 levels which may attenuate cellular proliferation.

Original languageEnglish (US)
Pages (from-to)803-808
Number of pages6
JournalBiochemical Journal
Volume281
Issue number3
StatePublished - 1992
Externally publishedYes

Fingerprint

Heparin
Phosphatidylinositols
Glycosaminoglycans
Vascular Smooth Muscle
Smooth Muscle Myocytes
Muscle
Brain
Phosphotransferases
Membranes
Phosphatidylinositol Phosphates
Polynucleotides
Dextran Sulfate
1-Phosphatidylinositol 4-Kinase
Guanine Nucleotides
Heparitin Sulfate
1-phosphatidylinositol-4-phosphate 5-kinase
Chondroitin Sulfates
antineoplaston A10
Cell growth
Pathologic Processes

ASJC Scopus subject areas

  • Biochemistry

Cite this

Inhibition of phosphatidylinositol 4-phosphate kinase by heparin. A possible mechanism for the antiproliferative effects of heparin. / Smith, C. D.; Wen, D.; Mooberry, Susan L; Chang, K. J.

In: Biochemical Journal, Vol. 281, No. 3, 1992, p. 803-808.

Research output: Contribution to journalArticle

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