title: Lnk adaptor suppresses radiation resistance and radiation-induced B-cell malignancies by inhibiting IL-11 signaling.
abstract: The Lnk (Sh2b3) adaptor protein dampens the response of hematopoietic stem cells and progenitors (HSPCs) to a variety of cytokines by inhibiting JAK2 signaling. As a consequence, Lnk(-/-) mice develop hematopoietic hyperplasia, which progresses to a phenotype resembling the nonacute phase of myeloproliferative neoplasm. In addition, Lnk mutations have been identified in human myeloproliferative neoplasms and acute leukemia. We find that Lnk suppresses the development of radiation-induced acute B-cell malignancies in mice. Lnk-deficient HSPCs recover more effectively from irradiation than their wild-type counterparts, and this resistance of Lnk(-/-) HSPCs to radiation underlies the subsequent emergence of leukemia. A search for the mechanism responsible for radiation resistance identified the cytokine IL-11 as being critical for the ability of Lnk(-/-) HSPCs to recover from irradiation and subsequently become leukemic. In IL-11 signaling, wild-type Lnk suppresses tyrosine phosphorylation of the Src homology region 2 domain-containing phosphatase-2/protein tyrosine phosphatase nonreceptor type 11 and its association with the growth factor receptor-bound protein 2, as well as activation of the Erk MAP kinase pathway. Indeed, Src homology region 2 domain-containing phosphatase-2 has a binding motif for the Lnk Src Homology 2 domain that is phosphorylated in response to IL-11 stimulation. IL-11 therefore drives a pathway that enhances HSPC radioresistance and radiation-induced B-cell malignancies, but is normally attenuated by the inhibitory adaptor Lnk.
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5.
authors.forename: Igal
authors.initials: I
authors.lastname: Louria-Hayon
authors.forename: Catherine
authors.initials: C
authors.lastname: Frelin
authors.forename: Julie
authors.initials: J
authors.lastname: Ruston
authors.forename: Gerald
authors.initials: G
authors.lastname: Gish
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.forename: Michael M
authors.initials: MM
authors.lastname: Kofler
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Lambert
authors.forename: Hibret A
authors.initials: HA
authors.lastname: Adissu
authors.forename: Michael
authors.initials: M
authors.lastname: Milyavsky
authors.forename: Robert
authors.initials: R
authors.lastname: Herrington
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
authors.forename: Norman N
authors.initials: NN
authors.lastname: Iscove
authors.forename: Tony
authors.initials: T
authors.lastname: Pawson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000818:Animals; D051380:GRB2 Adaptor Protein / Q000235:genetics / Q000378:metabolism; D005720:Gamma Rays / Q000009:adverse effects*; D006801:Humans; D017370:Interleukin-11 / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D015448:Leukemia, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000528:radiation effects*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance / Q000235:genetics / Q000528:radiation effects*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C508611:IL11 protein, human; D017370:Interleukin-11; D047908:Intracellular Signaling Peptides and Proteins; C490777:Lnk protein, mouse; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011506:Proteins; C490778:SH2B3 protein, human; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse
keywords: cancer; gp130; lymphoma; survival