Normalization of TAM post-receptor signaling reveals a cell invasive signature for Axl tyrosine kinase.
Tyro3, Axl, and Mertk (TAMs) are a family of three conserved receptor tyrosine kinases that have pleiotropic roles in innate immunity and homeostasis and when overexpressed in cancer cells can drive tumorigenesis.



In the present study, we engineered EGFR/TAM chimeric receptors (EGFR/Tyro3, EGFR/Axl, and EGF/Mertk) with the goals to interrogate post-receptor functions of TAMs, and query whether TAMs have unique or overlapping post-receptor activation profiles. Stable expression of EGFR/TAMs in EGFR-deficient CHO cells afforded robust EGF inducible TAM receptor phosphorylation and activation of downstream signaling.



Using a series of unbiased screening approaches, that include kinome-view analysis, phosphor-arrays, RNAseq/GSEA analysis, as well as cell biological and in vivo readouts, we provide evidence that each TAM has unique post-receptor signaling platforms and identify an intrinsic role for Axl that impinges on cell motility and invasion compared to Tyro3 and Mertk.



These studies demonstrate that TAM show unique post-receptor signatures that impinge on distinct gene expression profiles and tumorigenic outcomes.
Rutgers, Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers- New Jersey Medical School, 205 South Orange Ave, Newark, NJ, 07103, USA.
Stanley G
SG
Kimani
Rutgers, Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers- New Jersey Medical School, 205 South Orange Ave, Newark, NJ, 07103, USA.
Sushil
S
Kumar
Rutgers, Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers- New Jersey Medical School, 205 South Orange Ave, Newark, NJ, 07103, USA.
Viralkumar
V
Davra
Rutgers, Biomedical and Health Sciences, OIT/High Performance and Research Computing, 185 South Orange Ave, Newark, NJ, 07103, USA.
Yun-Juan
YJ
Chang
Rutgers, Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers- New Jersey Medical School, 205 South Orange Ave, Newark, NJ, 07103, USA.
Canan
C
Kasikara
Rutgers, Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers- New Jersey Medical School, 205 South Orange Ave, Newark, NJ, 07103, USA.
Ke
K
Geng
Rutgers, Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers- New Jersey Medical School, 205 South Orange Ave, Newark, NJ, 07103, USA.
Wen-I
WI
Tsou
Rutgers, Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers- New Jersey Medical School, 205 South Orange Ave, Newark, NJ, 07103, USA.
Shenyan
S
Wang
Rutgers, Department of Microbiology, Biochemistry and Molecular Genetics, Genomics Research Program, Rutgers- New Jersey Medical School, 185 South Orange Ave, Newark, NJ, 07103, USA.
Mainul
M
Hoque
Department of Organic Chemistry, Comenius University in Bratislava, Faculty of Natural Sciences, Mlynská dolina, Ilkovičova 6, 842 15, Bratislava, Slovakia.|Biomagi, Ltd, Mamateyova 26, 851 04, Bratislava, Slovakia.
Andrej
A
Boháč
Rutgers, Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers- New Jersey Medical School, 205 South Orange Ave, Newark, NJ, 07103, USA.
Anita
A
Lewis-Antes
Rutgers, Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers- New Jersey Medical School, 205 South Orange Ave, Newark, NJ, 07103, USA.
Mariana S
MS
De Lorenzo
Rutgers, Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers- New Jersey Medical School, 205 South Orange Ave, Newark, NJ, 07103, USA.
Sergei V
SV
Kotenko
Rutgers, Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, Rutgers- New Jersey Medical School, 205 South Orange Ave, Newark, NJ, 07103, USA. birgera@njms.rutgers.edu.
Raymond B
RB
Birge
D000818:Animals; D016466:CHO Cells; D002465:Cell Movement; D006224:Cricetinae; D003412:Cricetulus; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase
D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; C513478:Tyro3 protein, mouse; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase
Invasion; Metastasis; Signaling; TAM RTKs