Deletion of an N-terminal regulatory domain of the c-abl tyrosine kinase activates its oncogenic potential.

Franz, Wolfgang-M.; Berger, Paul; Wang, J. Y. J.

doi:10.1002/j.1460-2075.1989.tb03358.x

Cited by 196 publications

(176 citation statements)

References 48 publications

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“…Because the Abl SH3 domain has been implicated in the repression of c-Abl activity (BarilaÂ and SupertiFurga, 1998;Franz et al, 1989;Jackson and Baltimore, 1989;Van Etten et al, 1995), and has been shown to bind to Cbl (Shishido et al, 2000), we examined whether the PRD1 region of Cbl speci®cally interacts with the Abl SH3. As shown in Figure 3a, the SH3 domain of Abl bound directly to full-length Cbl, but not to deletion mutants lacking PRD-1, when assayed in`far-Western' ®lter-binding experiments.…”

Section: Cbl Engages C-abl and Is Phosphorylated By Itmentioning

confidence: 99%

“…Normally c-Abl activity is tightly repressed, as overexpression does not lead to e cient transformation or increased tyrosine phosphorylation of cell proteins (Franz et al, 1989;Jackson and Baltimore, 1989). This negative regulation is mediated at least in part by the SH3 domain, as deleting, mutating, or altering the position of the SH3 is su cient to activate the kinase and transforming activities of Abl (Franz et al, 1989; Jackson and Baltimore, 1989;Mayer and Baltimore, 1994;Van Etten et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

“…This negative regulation is mediated at least in part by the SH3 domain, as deleting, mutating, or altering the position of the SH3 is su cient to activate the kinase and transforming activities of Abl (Franz et al, 1989; Jackson and Baltimore, 1989;Mayer and Baltimore, 1994;Van Etten et al, 1995). The precise mechanism whereby the SH3 domain regulates the kinase activity of Abl is still unknown, however.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Cbl phosphorylation by the Abl tyrosine kinase and the Nck SH2/SH3 adaptor

et al. 2001

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The Cbl proto-oncogene product is tyrosine phosphorylated in response to a wide variety of stimuli. Cbl and the Abl nonreceptor tyrosine kinase both bind to SH3 domains from the SH2/SH3 adaptor Nck, and are candidate e ectors for Nck function. Numerous additional SH2-and SH3-domain-mediated interactions are also possible between Cbl, Abl, and Nck. We ®nd that these three signaling proteins associate when overexpressed in mammalian cells and can regulate each other's activity. Co-expression of wt Cbl together with cAbl, the activity of which is normally repressed in vivo, led to extensive Abl-dependent phosphorylation of Cbl. The major proline-rich region of Cbl was required for its phosphorylation by c-Abl, but not by a constitutively activated Abl mutant, suggesting Cbl activates c-Abl by engaging its SH3 domain. E cient phosphorylation of Cbl and its stable association with Abl required the SH2 domain of Abl, suggesting that SH2-phosphotyrosine interactions prevent dissociation of active Abl from Cbl. We also show that overexpression of Nck could repress the phosphorylation of Cbl by Abl in vivo. Studies with Nck mutants suggested that the Nck SH2 domain is responsible for inhibiting the activity of Abl toward both Cbl and Nck itself, most likely by competing with the Abl SH2 for tyrosine-phosphorylated binding sites. Oncogene (2001) 20, 4058 ± 4069.

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Section: Cbl Engages C-abl and Is Phosphorylated By Itmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Regulation of Cbl phosphorylation by the Abl tyrosine kinase and the Nck SH2/SH3 adaptor

et al. 2001

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“…16,17 The SH3 domain seems to be responsible for the functional inactivity of the ABL-portion of BCR/ABL. Hence, we created a mutant that lacks a functional SH3 domain (DSH3-ABL) alone and in combination with the T315I.…”

Section: Resultsmentioning

confidence: 99%

The gatekeeper mutation T315I confers resistance against small molecules by increasing or restoring the ABL-kinase activity accompanied by aberrant transphosphorylation of endogenous BCR, even in loss-of-function mutants of BCR/ABL

et al. 2009

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In Philadelphia chromosome-positive (Ph þ ) leukemia BCR/ ABL induces the leukemic phenotype. Targeted inhibition of BCR/ABL by kinase inhibitors leads to complete remission. However, patients with advanced Ph þ leukemia relapse and acquire resistance, mainly due to point mutations in BCR/ABL. The 'gatekeeper mutation' T315I is responsible for a general resistance to small molecules. It seems not only to decrease the affinity for kinase inhibitors, but to also confer additional features to the leukemogenic potential of BCR/ABL. To determine the role of T315I in resistance to the inhibition of oligomerization and in the leukemogenic potential of BCR/ABL, we investigated its influence on loss-of-function mutants with regard to the capacity to mediate factor independence. Here, we show that T315I (i) requires autophosphorylation at tyrosine 177 in the BCR-portion to mediate resistance against the inhibition of oligomerization; (ii) restores the capacity to mediate factor-independent growth of loss-of-function mutants due to an increase in or activation of ABL-kinase; (iii) leads to phosphorylation of endogenous BCR, suggesting aberrant substrate activation by BCR/ABL harboring the T315I mutation. These data show that T315I confers additional leukemogenic activity to BCR/ABL, which might explain the clinical behavior of patients with BCR/ABL-T315I-positive blasts.

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“…The observation that N-terminal mutations, especially within the SH3 domain, can activate the transforming activity of the normally nontransforming c-src and c-abl gene products (25)(26)(27)(28)(29) raised the possibility that SH3 might bind a kinase inhibitor. Ifthis were the case, the overexpressed SH3 domain of p47gam-crk might be expected to compete away such an inhibitor, leading to kinase activation in vivo.…”

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confidence: 99%

Association of the v-crk oncogene product with phosphotyrosine-containing proteins and protein kinase activity.

Mayer

Hanafusa

1990

Proc. Natl. Acad. Sci. U.S.A.

164

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An antiserum specific for p478gk, the oncogene product of avian sarcoma virus CT10, was used to investigate possible crk-binding proteins. In in vito kinase assays, four proteins were phosphorylated in anti-crk immunoprecipitates. Tyrosine, serine, and threonine residues were phosphorylated. A number of tyrosine-phosphorylated proteins were identified in anti-crk immunoprecipitates of 32p labeled cells, including the three major phosphotyrosinecontaining proteins of CT1O-infected cells. These three proteins also bound to bacterially synthesized crk protein. These results suggest that the crk transforming protein can stably associate with both endogenous kinases and cellular kinase substrates.

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Deletion of an N-terminal regulatory domain of the c-abl tyrosine kinase activates its oncogenic potential.

Cited by 196 publications

References 48 publications

Regulation of Cbl phosphorylation by the Abl tyrosine kinase and the Nck SH2/SH3 adaptor

Regulation of Cbl phosphorylation by the Abl tyrosine kinase and the Nck SH2/SH3 adaptor

The gatekeeper mutation T315I confers resistance against small molecules by increasing or restoring the ABL-kinase activity accompanied by aberrant transphosphorylation of endogenous BCR, even in loss-of-function mutants of BCR/ABL

Association of the v-crk oncogene product with phosphotyrosine-containing proteins and protein kinase activity.

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