AP-1 differentially expressed proteins Krp1 and fibronectin cooperatively enhance Rho-ROCK-independent mesenchymal invasion by altering the function, localization, and activity of nondifferentially expressed proteins.
The transcription factor AP-1, which is composed of Fos and Jun family proteins, plays an essential role in tumor cell invasion by altering gene expression. We report here that Krp1, the AP-1 up-regulated protein that has a role in pseudopodial elongation in v-Fos-transformed rat fibroblast cells, forms a novel interaction with the nondifferentially expressed actin binding protein Lasp-1. Krp1 and Lasp-1 colocalize with actin at the tips of pseudopodia, and this localization is maintained by continued AP-1 mediated down-regulation of fibronectin that in turn suppresses integrin and Rho-ROCK signaling and allows pseudopodial protrusion and mesenchyme-like invasion. Mutation analysis of Lasp-1 demonstrates that its SH3 domain is necessary for pseudopodial extension and invasion. The results support the concept of an AP-1-regulated multigenic invasion program in which proteins encoded by differentially expressed genes direct the function, localization, and activity of proteins that are not differentially expressed to enhance the invasiveness of cells.
Spence
Heather J
HJ
Invasion and Metastasis Laboratory, Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, United Kingdom. h.spence@beatson.gla.ac.uk
McGarry
Lynn
L
Chew
Catherine S
CS
Carragher
Neil O
NO
Scott-Carragher
Linda A
LA
Yuan
Zhengqiang
Z
Croft
Daniel R
DR
Olson
Michael F
MF
Frame
Margaret
M
Ozanne
Bradford W
BW
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D003598:Cytoskeletal Proteins; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D016762:Genes, fos; D047908:Intracellular Signaling Peptides and Proteins; D008648:Mesoderm / Q000378:metabolism; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D009361:Neoplasm Invasiveness; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011554:Pseudopodia / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D054460:rho-Associated Kinases
D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D005353:Fibronectins; D047908:Intracellular Signaling Peptides and Proteins; C405542:Klhl41 protein, rat; C495806:Lasp1 protein, rat; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases