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The Src homology 2 domain of Vav is required for its compartmentation to the plasma membrane and activation of c-Jun NH(2)-terminal kinase 1.

Arudchandran R, Brown MJ, Peirce MJ, Song JS, Zhang J, Siraganian RP, Blank U, Rivera J - J. Exp. Med. (2000)

Bottom Line: We found that Vav redistributes to the plasma membrane in response to Fcin receptor I (FcinRI) engagement.The FcinRI and Vav were found to colocalize and were recruited to glycosphingolipid-enriched microdomains (GEMs).Thus, Vav localization to the plasma membrane is mediated by its SH2 domain and may serve to regulate downstream effectors like JNK1.

View Article: PubMed Central - PubMed

Affiliation: Section on Chemical Immunology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

ABSTRACT
Vav is a hematopoietic cell-specific guanine nucleotide exchange factor (GEF) whose activation is mediated by receptor engagement. The relationship of Vav localization to its function is presently unclear. We found that Vav redistributes to the plasma membrane in response to Fcin receptor I (FcinRI) engagement. The redistribution of Vav was mediated by its Src homology 2 (SH2) domain and required Syk activity. The FcinRI and Vav were found to colocalize and were recruited to glycosphingolipid-enriched microdomains (GEMs). The scaffold protein, linker for activation of T cells (LAT), and Rac1 (a target of Vav activity) were constitutively present in GEMs. Expression of an SH2 domain-containing COOH-terminal fragment of Vav inhibited Vav phosphorylation and movement to the GEMs but had no effect on the tyrosine phosphorylation of the adaptor protein, SLP-76 (SH2 domain-containing leukocyte protein of 76 kD), and LAT. However, assembly of the multiprotein complex containing these proteins was inhibited. In addition, FcinRI-dependent activation of c-Jun NH(2)-terminal kinase 1 (JNK1) was also inhibited. Thus, Vav localization to the plasma membrane is mediated by its SH2 domain and may serve to regulate downstream effectors like JNK1.

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Model of Fc∈RI communication with Vav. Fc∈RI engagement results in Lyn phosphorylation of the ITAMs of the receptors and recruitment of receptors into GEMs  1. Which step occurs first is presently unclear. Syk is recruited to the phosphorylated ITAMs of Fc∈RI and is activated  2. Syk may target Vav for phosphorylation in the membrane or cytosol. Our data show the presence of phosphorylated Vav in both the cytosol and membrane, suggesting the possibility that phosphorylation may take place in the cytosol before membrane localization  3. Phosphorylated Vav can associate with the adaptor protein, SLP-76, which can mediate Vav movement to the GEMs because of SLP-76 binding to the scaffold protein, LAT, which is found in GEMs. Recruitment of Vav into these domains allows Vav to target Rac1 and activate it  4. Full activation of JNK1 via the Fc∈RI requires Vav activity.
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Figure 6: Model of Fc∈RI communication with Vav. Fc∈RI engagement results in Lyn phosphorylation of the ITAMs of the receptors and recruitment of receptors into GEMs 1. Which step occurs first is presently unclear. Syk is recruited to the phosphorylated ITAMs of Fc∈RI and is activated 2. Syk may target Vav for phosphorylation in the membrane or cytosol. Our data show the presence of phosphorylated Vav in both the cytosol and membrane, suggesting the possibility that phosphorylation may take place in the cytosol before membrane localization 3. Phosphorylated Vav can associate with the adaptor protein, SLP-76, which can mediate Vav movement to the GEMs because of SLP-76 binding to the scaffold protein, LAT, which is found in GEMs. Recruitment of Vav into these domains allows Vav to target Rac1 and activate it 4. Full activation of JNK1 via the Fc∈RI requires Vav activity.

Mentions: This study demonstrates that Vav moves to the plasma membrane upon Fc∈RI engagement ( Fig. 6). In addition, we found that most of the membrane-localized Vav and a portion of the Fc∈RI partition to LAT- and Rac1-containing GEMs ( Fig. 5 A), suggesting that these specialized membrane domains represent sites where receptors engage downstream effectors. Because Vav forms a complex with SLP-76 and LAT 9 19 44 45, our findings promote the view that Vav functions as part of a multiprotein signaling complex that is engaged by the Fc∈RI in the GEMs ( Fig. 6).


The Src homology 2 domain of Vav is required for its compartmentation to the plasma membrane and activation of c-Jun NH(2)-terminal kinase 1.

Arudchandran R, Brown MJ, Peirce MJ, Song JS, Zhang J, Siraganian RP, Blank U, Rivera J - J. Exp. Med. (2000)

Model of Fc∈RI communication with Vav. Fc∈RI engagement results in Lyn phosphorylation of the ITAMs of the receptors and recruitment of receptors into GEMs  1. Which step occurs first is presently unclear. Syk is recruited to the phosphorylated ITAMs of Fc∈RI and is activated  2. Syk may target Vav for phosphorylation in the membrane or cytosol. Our data show the presence of phosphorylated Vav in both the cytosol and membrane, suggesting the possibility that phosphorylation may take place in the cytosol before membrane localization  3. Phosphorylated Vav can associate with the adaptor protein, SLP-76, which can mediate Vav movement to the GEMs because of SLP-76 binding to the scaffold protein, LAT, which is found in GEMs. Recruitment of Vav into these domains allows Vav to target Rac1 and activate it  4. Full activation of JNK1 via the Fc∈RI requires Vav activity.
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Related In: Results  -  Collection

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Figure 6: Model of Fc∈RI communication with Vav. Fc∈RI engagement results in Lyn phosphorylation of the ITAMs of the receptors and recruitment of receptors into GEMs 1. Which step occurs first is presently unclear. Syk is recruited to the phosphorylated ITAMs of Fc∈RI and is activated 2. Syk may target Vav for phosphorylation in the membrane or cytosol. Our data show the presence of phosphorylated Vav in both the cytosol and membrane, suggesting the possibility that phosphorylation may take place in the cytosol before membrane localization 3. Phosphorylated Vav can associate with the adaptor protein, SLP-76, which can mediate Vav movement to the GEMs because of SLP-76 binding to the scaffold protein, LAT, which is found in GEMs. Recruitment of Vav into these domains allows Vav to target Rac1 and activate it 4. Full activation of JNK1 via the Fc∈RI requires Vav activity.
Mentions: This study demonstrates that Vav moves to the plasma membrane upon Fc∈RI engagement ( Fig. 6). In addition, we found that most of the membrane-localized Vav and a portion of the Fc∈RI partition to LAT- and Rac1-containing GEMs ( Fig. 5 A), suggesting that these specialized membrane domains represent sites where receptors engage downstream effectors. Because Vav forms a complex with SLP-76 and LAT 9 19 44 45, our findings promote the view that Vav functions as part of a multiprotein signaling complex that is engaged by the Fc∈RI in the GEMs ( Fig. 6).

Bottom Line: We found that Vav redistributes to the plasma membrane in response to Fcin receptor I (FcinRI) engagement.The FcinRI and Vav were found to colocalize and were recruited to glycosphingolipid-enriched microdomains (GEMs).Thus, Vav localization to the plasma membrane is mediated by its SH2 domain and may serve to regulate downstream effectors like JNK1.

View Article: PubMed Central - PubMed

Affiliation: Section on Chemical Immunology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

ABSTRACT
Vav is a hematopoietic cell-specific guanine nucleotide exchange factor (GEF) whose activation is mediated by receptor engagement. The relationship of Vav localization to its function is presently unclear. We found that Vav redistributes to the plasma membrane in response to Fcin receptor I (FcinRI) engagement. The redistribution of Vav was mediated by its Src homology 2 (SH2) domain and required Syk activity. The FcinRI and Vav were found to colocalize and were recruited to glycosphingolipid-enriched microdomains (GEMs). The scaffold protein, linker for activation of T cells (LAT), and Rac1 (a target of Vav activity) were constitutively present in GEMs. Expression of an SH2 domain-containing COOH-terminal fragment of Vav inhibited Vav phosphorylation and movement to the GEMs but had no effect on the tyrosine phosphorylation of the adaptor protein, SLP-76 (SH2 domain-containing leukocyte protein of 76 kD), and LAT. However, assembly of the multiprotein complex containing these proteins was inhibited. In addition, FcinRI-dependent activation of c-Jun NH(2)-terminal kinase 1 (JNK1) was also inhibited. Thus, Vav localization to the plasma membrane is mediated by its SH2 domain and may serve to regulate downstream effectors like JNK1.

Show MeSH