Surfactant protein A down-regulates epidermal growth factor receptor by mechanisms different from those of surfactant protein D

Abstract

We recently reported that the lectin surfactant protein D (SP-D) suppresses epidermal growth factor receptor (EGFR) signaling by interfering with ligand binding to EGFR through an interaction between the carbohydrate-recognition domain (CRD) of SP-D and -glycans of EGFR. Here, we report that surfactant protein A (SP-A) also suppresses EGF signaling in A549 human lung adenocarcinoma cells and in CHOK1 cells stably expressing human EGFR and that SP-A inhibits the proliferation and motility of the A549 cells. Results withI-EGF indicated that SP-A interferes with EGF binding to EGFR, and a ligand blot analysis suggested that SP-A binds EGFR in A549 cells. We also found that SP-A directly binds the recombinant extracellular domain of EGFR (soluble EGFR or sEGFR), and this binding, unlike that of SP-D, was not blocked by EDTA, excess mannose, or peptide:-glycosidase F treatment. We prepared a collagenase-resistant fragment (CRF) of SP-A, consisting of CRD plus the neck domain of SP-A, and observed that CRF directly binds sEGFR but does not suppress EGF-induced phosphorylation of EGFR in or proliferation of A549 cells. These results indicated that SP-A binds EGFR and down-regulates EGF signaling by inhibiting ligand binding to EGFR as well as SP-D. However, unlike for SP-D, SP-A lectin activity and EGFR -glycans were not involved in the interaction between SP-A and EGFR. Furthermore, our results suggested that oligomerization of SP-A is necessary to suppress the effects of SP-A on EGF signaling.

Surfactant Expression Defines an Inflamed Subtype of Lung Adenocarcinoma Brain Metastases that Correlates with Prolonged Survival

“…There are data, however, which suggest a favorable role of surfactant in primary lung cancer. Recent studies suggest that surfactant proteins A and B are able to suppress the progression in NSCLC (45,46), possibly through interaction with immune cells (46,47) or by reducing the activity of EGFR and thereby acting in a similar manner to tyrosine-kinase inhibitors (48). The role of NAPSA in lung cancer is much less established, but recent studies suggest that NAPSA could have a supportive function with regards to the effect of EGFR tyrosine kinase inhibitors (49).…”

Characteristics of surfactant proteins in tumorigenic and inflammatory lung lesions in rodents

“…They are produced by alveolar type II cells and Clara cells. SP-B and SP-C are hydrophobic proteins, which are essential for surface tension reduction 26 . SP-A and SP-D are hydrophilic proteins that belong to the C-type lectin superfamily 26 .…”

“…SP-B and SP-C are hydrophobic proteins, which are essential for surface tension reduction 26 . SP-A and SP-D are hydrophilic proteins that belong to the C-type lectin superfamily 26 . Studies on the expression of SP-A, SP-B, SP-C, and SP-D in lung tumors are rare.…”

Genetic disorders of the surfactant system: focus on adult disease

“…Thirdly, there is the role of the SP-A protein itself in preventing tumourigenesis. SP-A may suppress tumour development via recruitment and activation of natural killer cells and control of tumour-associated macrophage polarisation [130], or via epidermal growth factor receptor (EGFR) binding and down-regulation of epidermal growth factor (EGF) signalling [131]. Quantitative or qualitative changes due to SFTPA mutations may thus inhibit the protein's tumour suppressing abilities.…”