RasGRP4 is a novel Ras activator isolated from acute myeloid leukemia

Gary W. Reuther, Que T. Lambert, John F. Rebhun, Michael A. Caligiuri, Lawrence Quilliam, Channing J. Der

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Although a number of genetic defects are commonly associated with acute myeloid leukemia (AML), a large percentage of AML cases are cytogenetically normal. This suggests a functional screen for transforming genes is required to identify genetic mutations that are missed by cytogenetic analyses. We utilized a retrovirus-based cDNA expression system to identify transforming genes expressed in cytogenetically normal AML patients. We identified a new member of the Ras guanyl nucleotide-releasing protein (RasGRP) family of Ras guanine nucleotide exchange factors, designating it RasGRP4. Subsequently, cDNA sequences encoding rodent and human RasGRP4 proteins were deposited in GenBank™. RasGRP4 contains the same protein domain structure as other members of the RasGRP family, including a Ras exchange motif, a CDC25 homology domain, a C1/diacyglycerol-binding domain, and putative calcium-binding EF hands. We show that expression of RasGRP4 induces anchorage-independent growth of Rat1 fibroblasts. RasGRP4 is a Ras-specific activator and, interestingly, is highly expressed in peripheral blood leukocytes and myeloid cell lines. Unlike other RasGRP proteins, RasGRP4 is not expressed in the brain or in lymphoid cells. We demonstrated that 32D myeloid cells expressing RasGRP4 have elevated levels of activated Ras compared with control cells, and phorbol 12-myristate 13-acetate (PMA) treatment greatly enhanced Ras activation. PMA induced membrane localization of RasGRP4 and 32D cells expressing RasGRP4 were capable of cytokine-independent proliferation in the presence of PMA. We conclude that RasGRP4 is a member of the RasGRP family of Ras guanine nucleotide exchange factors that may play a role in myeloid cell signaling growth regulation pathways that are responsive to diacylglycerol levels.

Original languageEnglish
Pages (from-to)30508-30514
Number of pages7
JournalJournal of Biological Chemistry
Volume277
Issue number34
DOIs
StatePublished - Aug 23 2002

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Acute Myeloid Leukemia
ras Guanine Nucleotide Exchange Factors
Myeloid Cells
Nucleotides
Proteins
Acetates
Oncogenes
Cells
Complementary DNA
EF Hand Motifs
Genes
Cell signaling
Cytogenetic Analysis
Diglycerides
Nucleic Acid Databases
Retroviridae
Growth
Fibroblasts
Rodentia
Blood Cells

ASJC Scopus subject areas

  • Biochemistry

Cite this

Reuther, G. W., Lambert, Q. T., Rebhun, J. F., Caligiuri, M. A., Quilliam, L., & Der, C. J. (2002). RasGRP4 is a novel Ras activator isolated from acute myeloid leukemia. Journal of Biological Chemistry, 277(34), 30508-30514. https://doi.org/10.1074/jbc.M111330200

RasGRP4 is a novel Ras activator isolated from acute myeloid leukemia. / Reuther, Gary W.; Lambert, Que T.; Rebhun, John F.; Caligiuri, Michael A.; Quilliam, Lawrence; Der, Channing J.

In: Journal of Biological Chemistry, Vol. 277, No. 34, 23.08.2002, p. 30508-30514.

Research output: Contribution to journalArticle

Reuther, GW, Lambert, QT, Rebhun, JF, Caligiuri, MA, Quilliam, L & Der, CJ 2002, 'RasGRP4 is a novel Ras activator isolated from acute myeloid leukemia', Journal of Biological Chemistry, vol. 277, no. 34, pp. 30508-30514. https://doi.org/10.1074/jbc.M111330200
Reuther, Gary W. ; Lambert, Que T. ; Rebhun, John F. ; Caligiuri, Michael A. ; Quilliam, Lawrence ; Der, Channing J. / RasGRP4 is a novel Ras activator isolated from acute myeloid leukemia. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 34. pp. 30508-30514.
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