Abstract
LDC3/Dynarrestin, an aminothiazole derivative, is a recently developed small molecule, which binds protein tyrosine phosphatase interacting protein 51 (PTPIP51). PTPIP51 interacts with various proteins regulating different signaling pathways leading to proliferation and migration. Her2 positive breast cancer cells (SKBR3) express high levels of PTPIP51. Therefore, we investigated the effects of LDC3/Dynarrestin on PTPIP51 and its interactome with 12 different proteins of various signal pathways including the interaction with dynein in SKBR3 cells. The localization and semi-quantification of PTPIP51 protein and the Tyr176 phosphorylated PTPIP51 protein were evaluated. Protein-protein-interactions were assessed by Duolink proximity ligation assays. Interactions and the activation of signal transduction hubs were examined with immunoblots. LDC3/Dynarrestin led to an increased PTPIP51 tyrosine 176 phosphorylation status while the overall amount of PTPIP51 remained unaffected. These findings are paralleled by an enhanced interaction of PTPIP51 with its crucial kinase c-Src and a reduced interaction with the counteracting phosphatase PTP1B. Furthermore, the treatment results in a significantly augmented interaction of PTPIP51/14-3-3β and PTPIP51/Raf1, the link to the MAPK pathway. Under the influence of LDC3/Dynarrestin, the activity of the MAPK pathway rose in a concentration-dependent manner as indicated by RTK assays and immunoblots. The novel small molecule stabilizes the RelA/IκB/PTPIP51 interactome and can abolish the effects caused by TNFα stimulation. Moreover, LDC3/Dynarrestin completely blocked the Akt signaling, which is essential for tumor growth. The data were compared to the recently described interactome of PTPIP51 in LDC3/Dynarrestin treated non-cancerous keratinocyte cells (HaCaT). Differences were identified exclusively for the mitochondrial-associated ER-membranes (MAM) interactions and phospho-regulation related interactome of PTPIP51.LDC3/Dynarrestin gives the opportunity/possibility to influence the MAPK signaling, NFkB signaling and probably calcium homeostasis in breast cancer cells by affecting the PTPIP51 interactome.
Highlights
Breast cancer is the most common invasive cancerous disease amongst women
Since LDC3/Dynarrestin enhanced the formation of the Raf1/14.3.3β/protein tyrosine phosphatase interacting protein 51 (PTPIP51) complex, we further examined the influence of LDC3/Dynarrestin on the activation of the mitogen-activated protein kinase (MAPK) signaling pathway
(1) LDC3/Dynarrestin enhances the phosphorylation of Tyr176 of PTPIP51
Summary
Breast cancer is the most common invasive cancerous disease amongst women Prognosis of this disease is greatly influenced whether the Her2-oncogene/oncoprotein is amplified. This applies to 20–30% of the tumors [1]. Up to now different therapeutic antibodies and tyrosine kinase inhibitors (TKI) like Trastuzumab or Lapatinib have been developed to block the altered Her signaling by direct attachment to the Her receptor [3]. This targeted therapy led to significantly better results than radio- and chemotherapy alone [4,5]. In order to overcome such resistance, the identification of drugable PPIs and signal nodes downstream of Her is of the utmost interest
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