Pathway ID: SIGNOR-RMSView in NDEx

Description: Rhabdomyosarcoma (RMS) is a relatively rare cancer but is the most common form of soft-tissue sarcomas in young adults children and children. RMS can originate as a consequence of myogenic precursors failing to differentiate into normal muscle and is characterised by two major subtypes, embryonal RMS (ERMS) and alveolar RMS (ARMS). ERMS is the most common form of the disease, comprises about 60% of cases, and has a more favourable outcome than ARMS. It’s characterized by a wide range of genetic aberrations and the most frequent is the loss of heterozygosity at the 11p15 locus, a region that encodes insulin-like growth factor 2 (IGF2). ARMS is the most aggressive form of RMS with a poorer prognosis and more prone to metastasis. It’s characterized by genetic translocations that result in chimeric protein that fuse the DNA binding domain of the paired box proteins 3 or 7 (PAX3 or PAX7) to the transactivation domain of a forkhead transcription factor (FOXO1). RMS display many defects in growth-factor signalling pathways and cell-cycle checkpoints that lead to cell growth and proliferation. The most frequently affected pathways are fibroblast growth factor (FGF), insulin-like growth factor (IGF), hepatocyte growth factor, and platelet-derived growth factor. PAX-FOXO1 proteins can activate these pathways by transcriptional activation of IGFR1, FGFR4, MET (c-Met) and PDGFRA genes. In 93% of RMS cases there is an alteration of the receptor tyrosine kinase/RAS/ PI3K axis and that alterations appeared to hinge on the FGF and IGF pathways. FGF and IGF pathways converge on cell-cycle regulators such as the cell-cycle regulator p21 (CDKN1A), and the cell-cycle regulator p14 (CDKN2A). p21 is induced in myoblast differentiation and blocks cell-cycle progression ; is regulated by MyoD and myogenin in normal muscle cells and the inactivation of these proteins in RMS contributes to the silencing of p21. p14 is tumour suppressor and copy number deletions in CDKN2A were found in 2% of the RMS cancers. TBX2, a T-box gene family member, is overexpressed in both ERMS and ARMS cells. it is regulated by PAX3 and was found to induce a downregulation of p14 and to be a direct repressor of p21 in RMS.

Curated by: Marta Iannuccelli

complexity level

level 1 seed interactions
level 2 connect
level 3 first neighbors
level 4 all
level 5 PPI

39 Seed Entities

Name Primary ID
BRAF P15056
CDKN1A P38936
CDKN2A P42771
CTNNB1 P35222
FGF1 P05230
FGFR4 P22455
FOXO1 Q12778
GAB1 Q13480
GRB2 P62993
HGF P14210
IGF1 P05019
IGF1R P08069
IGF2 P01344
KRAS P01116
MET P08581
MYC P01106
MYOD1 P15172
MYOG P15173
PAX3 P23760
Pax3-FOXO1 J9SW06
PAX7 P23759
PDGFA P04085
PDGFB P01127
PDPK1 O15530
PIK3CA P42336
Proliferation SIGNOR-PH4
PtsIns(3,4,5)P3 CID:24755492
Skeletal Muscle Differentiation SIGNOR-PH1
SOS1 Q07889
SRC P12931
STAT3 P40763
Survival SIGNOR-PH13
TBX2 Q13207