Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis.

Abstract

We found that hematopoietic cell-specific Lyn substrate 1 (HCLS1 or HS1) is highly expressed in human myeloid cells and that stimulation with granulocyte colony-stimulating factor (G-CSF) leads to HCLS1 phosphorylation. HCLS1 binds the transcription factor lymphoid-enhancer binding factor 1 (LEF-1), transporting LEF-1 into the nucleus upon G-CSF stimulation and inducing LEF-1 autoregulation. In patients with severe congenital neutropenia, inherited mutations in the gene encoding HCLS1-associated protein X-1 (HAX1) lead to profound defects in G-CSF-triggered phosphorylation of HCLS1 and subsequently to reduced autoregulation and expression of LEF-1. Consistent with these results, HCLS1-deficient mice are neutropenic. In bone marrow biopsies of the majority of tested patients with acute myeloid leukemia, HCLS1 protein expression is substantially elevated, associated with high levels of G-CSF synthesis and, in some individuals, a four-residue insertion in a proline-rich region of HCLS1 protein known to accelerate intracellular signaling. These data demonstrate the importance of HCLS1 in myelopoiesis in vitro and in vivo.

• Authors: Julia Skokowa, Maxim Klimiankou, Olga Klimenkova, Dan Lan, Kshama Gupta, Kais Hussein, Esteban Carrizosa, Inna Kusnetsova, Zhixiong Li, Claudio Sustmann, Arnold Ganser, Cornelia Zeidler, Hans-Heinrich Kreipe, Janis Burkhardt, Rudolf Grosschedl, Karl Welte
• Journal: Nature medicine (Nat Med) Vol. 18 Issue 10 Pg. 1550-9 (Oct 2012) ISSN: 1546-170X [Electronic] United States
• PMID: 23001182 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Blood Proteins
• HAX1 protein, human
• HCLS1 protein, human
• LEF1 protein, human
• Lymphoid Enhancer-Binding Factor 1
• RNA, Small Interfering
• Receptors, Granulocyte Colony-Stimulating Factor
• Granulocyte Colony-Stimulating Factor

Topics

• Active Transport, Cell Nucleus
• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Animals
• Base Sequence
• Blood Proteins (genetics, metabolism)
• Cell Line
• Cell Proliferation
• Congenital Bone Marrow Failure Syndromes
• Female
• Granulocyte Colony-Stimulating Factor (metabolism)
• Granulocytes (metabolism)
• HEK293 Cells
• Humans
• Leukemia, Myeloid, Acute (genetics, metabolism)
• Lymphoid Enhancer-Binding Factor 1 (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mutation
• Myelopoiesis (genetics)
• Neutropenia (congenital, genetics, physiopathology)
• Phosphorylation
• RNA Interference
• RNA, Small Interfering
• Receptors, Granulocyte Colony-Stimulating Factor (genetics)
• Sequence Analysis, DNA
• Signal Transduction