'Srcasm: a Novel SrcActivating and SignalingMolecule

Seykora, John T.; Mei, Lijuan; Dotto, G. Paolo; Stein, Paul L.

doi:10.1074/jbc.m106813200

Cited by 50 publications

(87 citation statements)

References 66 publications

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“…By the yeast twohybrid interaction screen of a murine keratinocyte library, Seykora et al (26) found that TOM1L1 interacts with Fyn. In the murine brain, the distribution of TOM1L1 mRNA is correlated with that of Fyn, and the result of co-transfecting Fyn and TOM1L1 suggests that Fyn phosphorylates TOM1L1 (26). Recently, it was observed that EGF receptor stimulation induces the tyrosine phosphorylation of TOM1L1 in keratinocytes.…”

Section: Discussionmentioning

confidence: 99%

TOM1L1 Is a Lyn Substrate Involved in FcϵRI Signaling in Mast Cells

Zhang¹,

Suzuki²,

Hitomi³

et al. 2007

Journal of Biological Chemistry

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Protein-tyrosine kinase Lyn and Syk are critical for antigenreceptor-induced signal transduction in mast cells. To identify novel Lyn/Syk substrates, we screened an RBL-2H3 bacterial expression library for proteins that were tyrosine phosphorylated with baculoviral expressed Lyn or Syk. Five clones as potential Lyn substrates and eight clones as Syk substrates were identified including known substrates such as SLP-76, LAT, and ␣-tubulin. A potential substrate of Lyn identified was the molecule TOM1L1, which has several domains thought to be important for membrane trafficking and protein-protein interactions. Because the function of TOM1L1 is unclear, the rat TOM1L1 full-length cDNA was isolated and used to express the protein in COS-1 and RBL-2H3 mast cells. In COS-1 cells, the co-transfection of TOM1L1 and Lyn, but not Syk, resulted in the tyrosine phosphorylation of TOM1L1. In RBL-2H3 mast cells, the overexpressed TOM1L1 was strongly tyrosine phosphorylated in non-stimulated cells, and this phosphorylation was enhanced by Fc⑀RI aggregation. By subcellular fractionation, wild-type TOM1L1 was mainly in the cytoplasm with a small fraction constitutively associated with the membrane; this association was markedly reduced in deletion mutants lacking several of the protein interaction domains. The overexpression of TOM1L1 enhanced antigen-induced tumor necrosis factor (TNF) ␣ generation and release. Both protein interaction domains (VHS and the coiled-coil domains) were required for the increased TNF␣ release, but not the increased TNF␣ generation. These results suggest that TOM1L1 is a novel protein involved in the Fc⑀RI signal transduction for the generation of cytokines.The aggregation of the high affinity IgE receptor (Fc⑀RI) on mast cells and basophils activates multiple signaling pathways that lead to degranulation and the release of mediators of allergic reactions. The earliest biochemical event following Fc⑀RI aggregation is the tyrosine phosphorylation of multiple signaling molecules (1, 2). Because Fc⑀RI lacks intrinsic enzymatic activity, this phosphorylation is due to the rapid activation of two non-receptor-type protein-tyrosine kinases, Lyn and Syk. In this pathway Fc⑀RI aggregation results in Lyn phosphorylating the Tyr residues of the immunoreceptor tyrosine-based activation motifs of the ␤ and ␥ subunits of Fc⑀RI. The tyrosinephosphorylated immunoreceptor tyrosine-based activation motifs of the ␤ and ␥ subunits then recruit Lyn and Syk, respectively, through Src homology-2 (SH2) 5 domain-mediated interactions, leading to phosphorylation and activation of Syk (3-5).Because of their critical role in signal transduction, there is much interest in understanding how Lyn and Syk transfer the signal from Fc⑀RI aggregation to downstream events. Several substrates of Lyn and Syk have been identified by different experimental approaches. These include enzymes such as phospholipase C␥ (6), phospholipase D (7), Btk (8 -10), Pyk2 (11), Vav (12), phosphatidylinositol 3-kinase (13), and Cbl (14) To identify novel ...

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Section: Discussionmentioning

confidence: 99%

TOM1L1 Is a Lyn Substrate Involved in FcϵRI Signaling in Mast Cells

Zhang¹,

Suzuki²,

Hitomi³

et al. 2007

Journal of Biological Chemistry

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“…Src-activating and signaling molecule (Srcasm) is a substrate and negative regulator of SFKs (66,67). Srcasm has been shown to limit keratinocyte proliferation, promote differentiation, and negatively regulate EGFR and SFK signaling in primary human keratinocytes (68,69).…”

Section: Pathophysiologic Features Of Csccs Ras Family Members Of Prmentioning

confidence: 99%

From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma

Ratushny

Gober²,

Hick³

et al. 2012

J. Clin. Invest.

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489

477

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Cutaneous squamous cell carcinoma (cSCC) is the second most common human cancer with over 250,000 new cases annually in the US and is second in incidence only to basal cell carcinoma. cSCC typically manifests as a spectrum of progressively advanced malignancies, ranging from a precursor actinic keratosis (AK) to squamous cell carcinoma (SCC) in situ (SCCIS), invasive cSCC, and finally metastatic SCC. In this Review we discuss clinical and molecular parameters used to define this range of cutaneous neoplasia and integrate these with the multiple experimental approaches used to study this disease. Insights gained from modeling cSCCs have suggested innovative therapeutic targets for treating these lesions.

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“…Localization of Fyn on Endosomes after EGF Internalization-It has been described previously that Srcasm (Src activating and signaling molecule), the mouse homolog of Tom1L1, is capable of interacting with Fyn, Grb2, and the regulatory subunit of phosphoinositide 3-kinase, p85, in a phosphorylationdependent manner through several SH2 and SH3 domains located in the C-terminal portion of Srcasm (40). The motifs responsible for these interactions are conserved between mouse and human, indicating that Tom1L1 is probably also able to bind the same proteins.…”

Section: Tom1l1mentioning

confidence: 99%

“…In the present work, we characterize the interaction of Tom1L1 with TSG101 and Hrs, as well as the recruitment of Tom1L1 to endosomes after Hrs or active Fyn overexpression. We feel the presence of motifs in the Tom1L1 C-terminal region that mediates interactions with signaling proteins, such as the tyrosine kinase Fyn and Grb-2, and the regulatory subunit of phosphoinositide 3-kinase, p85 (40), makes this protein an excellent candidate to connect signaling and degradative pathways.…”

mentioning

confidence: 99%

Interactions of TOM1L1 with the Multivesicular Body Sorting Machinery

Puertollano

2005

Journal of Biological Chemistry

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Tom1L1 (Tom1-like1) and related proteins Tom1 (Target of Myb1) and Tom1L2 (Tom1-like2) constitute a new protein family characterized by the presence of a VHS (Vps27p/Hrs/Stam) domain in the N-terminal portion followed by a GAT (GGA and Tom) domain. Recently it was demonstrated that the GAT domain of both Tom1 and Tom1L1 binds ubiquitin, suggesting that these proteins might participate in the sorting of ubiquitinated proteins into multivesicular bodies (MVBs). Here we report a novel interaction between Tom1L1 and members of the MVB sorting machinery. Specifically, we found that the VHS domain of Tom1L1 interacts with Hrs (Hepatocyte growth factor-regulated tyrosine kinase substrate), whereas a PTAP motif, located between the VHS and GAT domain of Tom1L1, is responsible for binding to TSG101 (tumor susceptibility gene 101). Myc epitopetagged Tom1L1 showed a cytosolic distribution but was recruited to endosomes following Hrs expression. In addition, Tom1L1 possesses several tyrosine motifs at the C-terminal region that mediate interactions with members of the Src family kinases and other signaling proteins such as Grb2 and p85. We showed that a fraction of Fyn kinase localizes at endosomes and that this distribution becomes more evident after epidermal growth factor internalization. Moreover, expression of a constitutive active form of Fyn also promoted the recruitment of Tom1L1 to enlarged endosomes. Taken together, we propose that Tom1L1 could act as an intermediary between signaling and degradative pathways.Regulated degradation of cell surface proteins, particularly receptors involved in signaling pathways, is essential for the control of many biological processes, including cell proliferation, survival, migration, and differentiation (1, 2). Internalized membrane-protein cargo can be delivered either to recycling vesicles for transport back to the cell surface or to late endosomes for transfer to lysosomes and degradation. Multivesicular bodies (MVBs) 1 are the compartments where this sorting event takes place (3). Thus, proteins to be degraded are included into small vesicles that invaginate into the lumen of the endosome. Subsequent fusion of MVBs with lysosomes releases these vesicles into the lysosome lumen, where they are degraded by lysosomal hydrolases. In contrast, proteins that remain in the limiting membrane of MVBs are recycled to the trans-Golgi network (TGN) or plasma membrane. In the last few years, a number of genetic and biochemical studies have allowed the characterization of the molecular machinery implicated in the formation of MVBs. Hrs appears to be the first protein to be recruited to endosomes (4 -6) through an interaction of its FIVE domain with phosphatidylinositol 3-phosphate (7), a lipid highly enriched in endosomal membranes (8). This is followed by the consecutive recruitment of three multisubunit complexes termed ESCRT-I (9), ESCRT-II (10), and ESCRT-III (11). Finally, the AAA-type ATPase Vps4 binds ESCRT-III and, following MVB vesicle formation, promotes the dissociation of the E...

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'Srcasm: a Novel SrcActivating and SignalingMolecule

Cited by 50 publications

References 66 publications

TOM1L1 Is a Lyn Substrate Involved in FcϵRI Signaling in Mast Cells

TOM1L1 Is a Lyn Substrate Involved in FcϵRI Signaling in Mast Cells

From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma

Interactions of TOM1L1 with the Multivesicular Body Sorting Machinery

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