Gain- and loss-of-function Lyn mutant mice define a critical inhibitory role for Lyn in the myeloid lineage.
To investigate the role of the Lyn kinase in establishing signaling thresholds in hematopoietic cells, a gain-of-function mutation analogous to the Src Y527F-activating mutation was introduced into the Lyn gene. Intriguingly, although Lyn is widely expressed within the hematopoietic system, these mice displayed no propensity toward hematological malignancy. By contrast, analysis of aging cohorts of both loss- and gain-of-function Lyn mutant mice revealed that Lyn(-/-) mice develop splenomegaly, increased numbers of myeloid progenitors, and monocyte/macrophage (M phi) tumors. Biochemical analysis of cells from these mutants revealed that Lyn is essential in establishing ITIM-dependent inhibitory signaling and for activation of specific protein tyrosine phosphatases within myeloid cells. Loss of such inhibitory signaling may predispose mice lacking this putative protooncogene to tumorigenesis.
Harder
K W
KW
Ludwig Institute for Cancer Research, Melbourne Tumor Biology Branch, Royal Melbourne Hospital, Melbourne, Victoria 3050, Australia.
Parsons
L M
LM
Armes
J
J
Evans
N
N
Kountouri
N
N
Clark
R
R
Quilici
C
C
Grail
D
D
Hodgson
G S
GS
Dunn
A R
AR
Hibbs
M L
ML
D000375:Aging; D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D019070:Cell Lineage; D002478:Cells, Cultured; D003115:Colony-Stimulating Factors / Q000494:pharmacology; D019337:Hematologic Neoplasms / Q000209:etiology* / Q000473:pathology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D008954:Models, Biological; D009154:Mutation; D022423:Myeloid Cells / Q000502:physiology*; D023461:Myeloid Progenitor Cells / Q000502:physiology; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D013154:Spleen / Q000473:pathology; D013163:Splenomegaly / Q000209:etiology / Q000473:pathology; D019061:src-Family Kinases / Q000235:genetics* / Q000502:physiology*
D003115:Colony-Stimulating Factors; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D017027:Protein Tyrosine Phosphatases