Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The non-receptor tyrosine kinase SRC is frequently deregulated in human colorectal cancer (CRC), and SRC increased activity has been associated with poor clinical outcomes. In nude mice engrafted with human CRC cells, SRC over-expression favors tumor growth and is accompanied by a robust increase in tyrosine phosphorylation in tumor cells. How SRC contributes to this tumorigenic process is largely unknown. We analyzed SRC oncogenic signaling in these tumors by means of a novel quantitative proteomic analysis. This method is based on stable isotope labeling with amino acids of xenograft tumors by the addition of [(13)C(6)]-lysine into mouse food. An incorporation level greater than 88% was obtained in xenograft tumors after 30 days of the heavy lysine diet. Quantitative phosphoproteomic analysis of these tumors allowed the identification of 61 proteins that exhibited a significant increase in tyrosine phosphorylation and/or association with tyrosine phosphorylated proteins upon SRC expression. These mainly included molecules implicated in vesicular trafficking and signaling and RNA binding proteins. Most of these proteins were specific targets of SRC signaling in vivo, as they were not identified by analysis via stable isotope labeling by amino acids in cell culture (SILAC) of the same CRC cells in culture. This suggests that oncogenic signaling induced by SRC in tumors significantly differs from that induced by SRC in cell culture. We next confirmed this notion experimentally with the example of the vesicular trafficking protein and SRC substrate TOM1L1. We found that whereas TOM1L1 depletion only slightly affected SRC-induced proliferation of CRC cells in vitro, it drastically decreased tumor growth in xenografted nude mice. We thus concluded that this vesicular trafficking protein plays an important role in SRC-induced tumor growth. Overall, these data show that SILAC analysis in mouse xenografts is a valuable approach for deciphering tyrosine kinase oncogenic signaling in vivo.
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PMID:Analysis of SRC oncogenic signaling in colorectal cancer by stable isotope labeling with heavy amino acids in mouse xenografts. 2302 24

ERBB2 overexpression in human breast cancer leads to invasive carcinoma but the mechanism is not clearly understood. Here we report that TOM1L1 is co-amplified with ERBB2 and defines a subgroup of HER2(+)/ER(+) tumours with early metastatic relapse. TOM1L1 encodes a GAT domain-containing trafficking protein and is a SRC substrate that negatively regulates tyrosine kinase signalling. We demonstrate that TOM1L1 upregulation enhances the invasiveness of ERBB2-transformed cells. This pro-tumoural function does not involve SRC, but implicates membrane-bound membrane-type 1 MMP (MT1-MMP)-dependent activation of invadopodia, membrane protrusions specialized in extracellular matrix degradation. Mechanistically, ERBB2 elicits the indirect phosphorylation of TOM1L1 on Ser321. The phosphorylation event promotes GAT-dependent association of TOM1L1 with the sorting protein TOLLIP and trafficking of the metalloprotease MT1-MMP from endocytic compartments to invadopodia for tumour cell invasion. Collectively, these results show that TOM1L1 is an important element of an ERBB2-driven proteolytic invasive programme and that TOM1L1 amplification potentially enhances the metastatic progression of ERBB2-positive breast cancers.
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PMID:TOM1L1 drives membrane delivery of MT1-MMP to promote ERBB2-induced breast cancer cell invasion. 2689 82

Cryopreservation causes significant lethal and sub-lethal damage to spermatozoa. In order to improve freezing outcomes, a comprehensive understanding of sub-lethal damage is required. Cryopreservation induced changes to sperm proteins have been investigated in several species, but few have employed currently available state of the art, data independent acquisition mass spectrometry (MS) methods. We used the SWATH LC-MS method to quantitatively profile proteomic changes to ram spermatozoa following exposure to egg yolk and cryopreservation. Egg yolk contributed 15 proteins to spermatozoa, including vitellogenins, apolipoproteins and complement component C3. Cryopreservation significantly altered the abundance of 51 proteins. Overall, 27 proteins increased (e.g. SERPINB1, FER) and 24 proteins decreased (e.g. CCT subunits, CSNK1G2, TOM1L1) in frozen thawed ram spermatozoa, compared to fresh spermatozoa. Chaperones constituted 20% of the proteins lost from spermatozoa following cryopreservation. These alterations may interfere with both normal cellular functioning and the ability of frozen thawed spermatozoa to appropriately respond to stress. This is the first study to apply SWATH mass spectrometry techniques to characterise proteins contributed by egg yolk based freezing media and to profile cryopreservation induced proteomic changes to ram spermatozoa.
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PMID:Cryopreservation and egg yolk medium alter the proteome of ram spermatozoa. 2962 24